Bisaryl-bonded aryltriazolones and use thereof

ABSTRACT

The present application relates to novel bisaryl-linked 5-aryl-1,2,4-triazolone derivatives, to processes for preparing them, to their use alone or in combinations for the treatment and/or prevention of diseases and also to their use for the production of medicaments for the treatment and/or prevention of diseases, more particularly for the treatment and/or prevention of cardiovascular disorders.

The present application relates to novel bisaryl-linked5-aryl-1,2,4-triazolone derivatives, to processes for preparing them, totheir use alone or in combinations for the treatment and/or preventionof diseases and also to their use for the production of medicaments forthe treatment and/or prevention of diseases, more particularly for thetreatment and/or prevention of cardiovascular disorders.

The liquid content of the human body is subject to various physiologicalcontrol mechanisms, the purpose whereof is to keep it constant (volumehomeostasis). In the process, both the volume filling of the vascularsystem and also the osmolarity of the plasma are continuously recordedby appropriate sensors (baroreceptors and osmoreceptors). Theinformation which these sensors supply to the relevant centers in thebrain regulates drinking behavior and controls fluid excretion via thekidneys by means of humoral and neural signals. The peptide hormonevasopressin is of central importance in this [Schrier R. W., Abraham, W.T., New Engl. J. Med. 341, 577-585 (1999)].

Vasopressin is produced in specialized endocrine neurons in the Nucleussupraopticus and N. paraventricularis in the wall of the third ventricle(hypothalamus) and transported from there along its neural processesinto the posterior lobes of the hypophysis (neurohypophysis). There thehormone is released into the bloodstream according to stimulus. A lossof volume, e.g. as a result of acute bleeding, heavy sweating, prolongedthirst or diarrhoea, is a stimulus for intensified outpouring of thehormone. Conversely, the secretion of vasopressin is inhibited by anincrease in the intravascular volume, e.g. as result of increased fluidintake.

Vasopressin exerts its action mainly via binding to three receptors,which are classified as V1a, V1b and V2 receptors and belong to thefamily of G protein-coupled receptors. V1a receptors are mainly locatedon the cells of the vascular smooth musculature. Their activation givesrise to vasoconstriction, as a result of which the peripheral resistanceand blood pressure rise. Apart from this, V1a receptors are alsodetectable in the liver. V1b receptors (also named V3 receptors) aredetectable in the central nervous system. Together withcorticotropin-releasing hormone (CRH), vasopressin regulates the basaland stress-induced secretion of adrenocorticotropic hormone (ACTH) viathe V1b receptor. V2 receptors are located in the distal tubularepithelium and the epithelium of the collecting tubules in the kidney.Their activation renders these epithelia permeable to water. Thisphenomenon is due to the incorporation of aquaporins (special waterchannels) in the luminal membrane of the epithelial cells.

The importance of vasopressin for the reabsorption of water from theurine in the kidney becomes clear from the clinical picture of diabetesinsipidus, which is caused by a deficiency of the hormone, e.g. owing tohypophysis damage. Patients who suffer from this clinical pictureexcrete up to 20 liters of urine per 24 hours if they are not givenreplacement hormone. This volume corresponds to about 10% of the primaryurine. Because of its great importance for the reabsorption of waterfrom the urine, vasopressin is also synonymously referred to asantidiuretic hormone (ADH). Logically, pharmacological inhibition of theaction of vasopressin/ADH on the V2 receptor results in increased urineexcretion. In contrast to the action of other diuretics (thiazides andloop diuretics), however, V2 receptor antagonists cause increased waterexcretion, without substantially increasing the excretion ofelectrolytes. This means that by means of V2 antagonist drugs, volumehomeostasis can be restored, without in the process affectingelectrolyte homeostasis. Hence drugs with V2 antagonist activity appearparticularly suitable for the treatment of all disease conditions whichare associated with an overloading of the body with water, without theelectrolytes being effectively increased in parallel. A significantelectrolyte abnormality is measurable in clinical chemistry ashyponatremia (sodium concentration <135 mmol/L); it is the mostimportant electrolyte abnormality in hospital patients, with anincidence of about 5% or 250 000 cases per year in the USA alone. If theplasma sodium concentration falls below 115 mmol/L, comatose states anddeath are imminent.

Depending on the underlying cause, a distinction is made betweenhypovolemic, euvolemic and hypervolemic hyponatremia. The forms ofhypervolemia with edema formation are clinically significant. Typicalexamples of this are the syndrome of inappropriate ADH/vasopressinsecretion (SIAD) (e.g. after craniocerebral trauma or as paraneoplasiain carcinomas) and hypervolemic hyponatremia in liver cirrhosis, variousrenal diseases and heart failure [De Luca L. et al., Am. J. Cardiol. 96(suppl.), 19L-23L (2005)]. In particular, patients with heart failure,in spite of their relative hyponatremia and hypervolemia, often displayelevated vasopressin levels, which is seen as the consequence ofgenerally disturbed neurohumoral regulation in heart failure [Francis G.S. et al., Circulation 82, 1724-1729 (1990)].

The disturbed neurohormonal regulation essentially manifests itself inan elevation of the sympathetic tone and inappropriate activation of therenin-angiotensin-aldosterone system. While the inhibition of thesecomponents by beta-receptor blockers on the one hand and by ACEinhibitors or angiotensin-receptor blockers on the other is now aninherent part of the pharmacological treatment of heart failure, theinappropriate elevation of vasopressin secretion in advanced heartfailure is at present still not adequately treatable. Apart from theretention of water mediated by V2 receptors and the unfavorablehemodynamic consequences associated therewith in terms of increasedbackload, the emptying of the left ventricle, the pressure in thepulmonary blood vessels and cardiac output are also adversely affectedby V1a-mediated vasoconstriction. Furthermore, on the basis ofexperimental data in animals, a direct hypertrophy-promoting action onthe heart muscle is also attributed to vasopressin. In contrast to therenal effect of volume expansion, which is mediated by activation of V2receptors, the direct action on the heart muscle is triggered byactivation of V1a receptors.

For these reasons, substances which inhibit the action of vasopressin onthe V2 and/or on the V1a receptor appear suitable for the treatment ofheart failure. In particular, compounds with combined activity on bothvasopressin receptors (V1a and V2) should both have desirable renal andalso hemodynamic effects and thus offer an especially ideal profile forthe treatment of patients with heart failure. The provision of suchcombined vasopressin antagonists also appears to make sense inasmuch asa volume diminution mediated solely via V2 receptor blockade can entailthe stimulation of osmoreceptors and as a result a further compensatoryincrease in vasopressin release. As a result, in the absence of acomponent simultaneously blocking the V1a receptor, the harmful effectsof the vasopressin, such as for example vasoconstriction and heartmuscle hypertrophy, could be further intensified [Saghi P. et al.,Europ. Heart J. 26, 538-543 (2005)].

It was an object of the present invention to provide novel compoundswhich act as potent selective or dual V1a/V2 receptor antagonists and assuch are suitable for the treatment and/or prevention of diseases, moreparticularly for the treatment and/or prevention of cardiovasculardisorders.

EP 0 412 594-A2, WO 92/20662-A1 and US 2001/0020100-A1 describe4-(biphenylalkyl)-1,2,4-triazolones having angiotensin II-antagonisticaction for the treatment of cardiovascular disorders. WO 99/31099-A1claims variously substituted 1,2,4-triazolones as therapeutically usefulintegrin receptor antagonists. The use of 5-aryl-1,2,4-triazolones asmedicaments with neuroprotective action is disclosed in WO 99/54315-A2,and WO 2006/117657-A1 describes 4,5-diaryltriazolone derivatives asantiinflammatory agents. WO 2006/078698-A1 claims various heterocycliccompounds as tyrosine phosphatase inhibitors for the treatment ofdiabetes. WO 2005/105779-A1 discloses 3-heterocyclyl-4-phenyltriazolesas inhibitors of the vasopressin V1A receptor, and WO 2007/134862-A1describes amidically attached 5-aryl-1,2,4-triazolones as dualvasopressin antagonists. WO 00/58306-A1 and WO 00/68227-A1 discloseheterocyclically substituted benzoylpyrazoles and -isoxazoles asherbicides.

The present invention provides compounds of the general formula (I)

in which

-   R¹ represents (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl or (C₂-C₆)-alkynyl,    each of which may be mono- to trisubstituted by identical or    different radicals selected from the group consisting of fluorine,    chlorine, cyano, trifluoromethyl, oxo, hydroxyl, difluoromethoxy,    trifluoromethoxy, (C₁-C₄)-alkoxy, (C₃-C₇)-cycloalkyl and phenyl,    -   where (C₃-C₇)-cycloalkyl may be substituted up to two times by        identical or different radicals selected from the group        consisting of fluorine, trifluoromethyl, (C₁-C₄)-alkyl, oxo,        hydroxyl, trifluoromethoxy and (C₁-C₄)-alkoxy    -   and    -   where phenyl may be substituted up to three times by identical        or different radicals selected from the group consisting of        halogen, cyano, nitro, difluoromethyl, trifluoromethyl,        (C₁-C₄)-alkyl, hydroxyl, hydroxymethyl, difluoromethoxy,        trifluoromethoxy, (C₁-C₄)-alkoxy, (C₁-C₄)-alkoxymethyl,        hydroxycarbonyl, (C₁-C₄)-alkoxycarbonyl, aminocarbonyl,        mono-(C₁-C₄)-alkylaminocarbonyl and        di-(C₁-C₄)-alkylaminocarbonyl,-    or-    represents (C₃-C₇)-cycloalkyl which may be mono- or disubstituted    by identical or different radicals selected from the group    consisting of fluorine, trifluoromethyl, (C₁-C₄)-alkyl, oxo,    hydroxyl, trifluoromethoxy and (C₁-C₄)-alkoxy,-   Ar¹ represents phenyl, thienyl or furyl, each of which may be mono-    to trisubstituted by identical or different radicals selected from    the group consisting of halogen, cyano, nitro, difluoromethyl,    trifluoromethyl, (C₁-C₄)-alkyl, hydroxyl, trifluoromethoxy and    (C₁-C₄)-alkoxy,-   L¹ represents the group —CH₂—, —C(═O)— or —SO₂—,-   Q represents a phenyl ring, a 5-membered heteroaryl ring having up    to three ring heteroatoms from the group consisting of N, O and S or    a 6-membered heteroaryl ring having up to three nitrogen ring atoms,-   R² represents a substituent selected from the group consisting of    fluorine, chlorine, bromine, cyano, nitro, (C₁-C₄)-alkyl,    (C₃-C₆)-cycloalkyl, phenyl, hydroxyl, (C₁-C₄)-alkoxy, amino,    aminocarbonylamino, (C₁-C₄)-alkylcarbonylamino, hydroxycarbonyl,    (C₁-C₄)-alkoxycarbonyl, aminocarbonyl,    mono-(C₁-C₄)-alkylaminocarbonyl and di-(C₁-C₄)-alkylaminocarbonyl,    -   where the (C₁-C₄)-alkyl substituent for its part may be        substituted by hydroxyl, (C₁-C₄)-alkoxy, carbamoyloxy,        hydroxycarbonyl, (C₁-C₄)-alkoxycarbonyl, aminocarbonyl,        mono-(C₁-C₄)-alkylaminocarbonyl or di-(C₁-C₄)-alkylaminocarbonyl        or up to three times by fluorine    -   and    -   where the phenyl substituent for its part may be substituted by        fluorine, chlorine, cyano, methyl, trifluoromethyl or methoxy,-   n represents the number 0, 1 or 2,    -   where in the case that the substituent R² occurs twice its        meanings may be identical or different,-   L² represents a bond, represents —O— or represents a group of the    formula —(CR^(3A)R^(3B))_(p)— in which    -   R^(3A) represents hydrogen, fluorine or methyl,    -   R^(3B) represents hydrogen, fluorine, (C₁-C₄)-alkyl,        hydroxycarbonyl, (C₁-C₄)-alkoxy-carbonyl or aminocarbonyl,        -   where (C₁-C₄)-alkyl may be substituted by hydroxyl or            carbamoyloxy or up to three times by fluorine,    -   or    -   R^(3A) and R^(3B) are attached to one another and together form        a —(CH₂)_(r) bridge in which        -   r represents the number 2, 3, 4 or 5        -   and a CH₂ group of this bridge may be replaced by —O—,    -   and    -   p represents the number 1 or 2,        -   where in the case that the group —CR^(3A)R^(3B)— occurs            twice the individual meanings of R^(3A) and R^(3B) may in            each case be identical or different,-   and-   Ar² represents phenyl, naphthyl or 5- to 10-membered heteroaryl    having up to three ring heteroatoms from the group consisting of N,    O and S, each of which may be mono- to tri-substituted by identical    or different radicals selected from the group consisting of halogen,    cyano, nitro, difluoromethyl, trifluoromethyl, (C₁-C₄)-alkyl,    hydroxyl, difluoromethoxy, trifluoromethoxy and (C₁-C₄)-alkoxy,    and salts, solvates and solvates of the salts thereof.

Compounds according to the invention are the compounds of the formula(I) and their salts, solvates, and solvates of the salts; the compoundsof the below-specified formulae embraced by formula (I), and theirsalts, solvates, and solvates of the salts; and also the compoundsspecified below as working examples and embraced by formula (I), andtheir salts, solvates, and solvates of the salts; insofar as thebelow-specified compounds embraced by formula (I) are not already salts,solvates, and solvates of the salts.

Depending on their structure, the compounds according to the inventionmay exist in different stereoisomeric forms, i.e. in the form ofconfigurational isomers or if appropriate also as conformational isomers(enantiomers and/or diastereomers, including those in the case ofatropisomers). The present invention therefore encompasses theenantiomers or diastereomers and the respective mixtures thereof. Thestereoisomerically uniform constituents can be isolated from suchmixtures of enantiomers and/or diastereomers in a known manner;chromatography processes are preferably used for this, in particularHPLC chromatography on an achiral or chiral phase.

Where the compounds according to the invention are able to occur intautomeric forms, the present invention embraces all of the tautomericforms.

The present invention also encompasses all suitable isotopic variants ofthe compounds according to the invention. An isotopic variant of acompound according to the invention is understood here to mean acompound in which at least one atom within the compound according to theinvention has been exchanged for another atom of the same atomic number,but with a different atomic mass than the atomic mass which usually orpredominantly occurs in nature. Examples of isotopes which can beincorporated into a compound according to the invention are those ofhydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine,chlorine, bromine and iodine, such as ²H (deuterium), ³H (tritium), ¹³C,¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³²P, ³³P, ³³S, ³⁴S, ³⁵S, ³⁶S, ¹⁸F, ³⁶Cl, ⁸²Br, ¹²³I,¹²⁴I, ¹²⁹I and ¹³¹I. Particular isotopic variants of a compoundaccording to the invention, especially those in which one or moreradioactive isotopes have been incorporated, may be beneficial, forexample, for the examination of the mechanism of action or of the activecompound distribution in the body; due to comparatively easypreparability and detectability, especially compounds labelled with ³Hor ¹⁴C isotopes are suitable for this purpose. In addition, theincorporation of isotopes, for example of deuterium, can lead toparticular therapeutic benefits as a consequence of greater metabolicstability of the compound, for example an extension of the half-life inthe body or a reduction in the active dose required; such modificationsof the compounds according to the invention may therefore in some casesalso constitute a preferred embodiment of the present invention.Isotopic variants of the compounds according to the invention can beprepared by generally used processes known to those skilled in the art,for example by the methods described below and the methods described inthe working examples, by using corresponding isotopic modifications ofthe particular reagents and/or starting compounds therein.

Salts preferred in the context of the present invention arephysiologically acceptable salts of the compounds of the invention. Alsoembraced are salts which, while not themselves suitable forpharmaceutical applications, may nevertheless be used, for example, forthe isolation, purification or storage of the compounds of theinvention.

Physiologically acceptable salts of the compounds of the inventionembrace acid addition salts of mineral acids, carboxylic acids andsulfonic acids, examples being salts of hydrochloric acid, hydrobromicacid, sulfuric acid, phosphoric acid, methanesulfonic acid,ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid,naphthalenedisulfonic acid, acetic acid, trifluoroacetic acid, propionicacid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid,maleic acid and benzoic acid.

Physiologically acceptable salts of the compounds of the invention alsoembrace salts with customary bases, such as—by way of example andpreferably—alkali metal salts (e.g. sodium and potassium salts),alkaline earth metal salts (e.g. calcium and magnesium salts) andammonium salts, derived from ammonia or from organic amines having 1 to16 C atoms, such as—by way of example and preferably—ethylamine,diethylamine, triethylamine, N,N-diisopropylethylamine,monoethanolamine, diethanolamine, Triethanolamine, dimethylaminoethanol,diethylaminoethanol, procaine, dicyclohexylamine, dibenzylamine,N-methylpiperidine, N-methylmorpholine, arginine, lysine and1,2-ethylendiamine.

Solvates in the context of the invention are those forms of thecompounds of the invention that form a complex in solid or liquid stateby coordination with solvent molecules. Hydrates are one specific formof solvates, where the coordination is with water. Preferred solvates inthe context of the present invention are hydrates.

Furthermore, the present invention also embraces prodrugs of thecompounds of the invention. The term “prodrugs” denotes compounds whichmay themselves be biologically active or inactive but which during theirresidence time in the body are converted (metabolically or byhydrolysis, for example) into compounds of the invention.

In the context of the present invention, the substituents, unlessotherwise specified, have the following definitions:

In the context of the invention, (C₁-C₆)-alkyl and (C₁-C₄)-alkylrepresent a straight-chain or branched alkyl radical having 1 to 6 and 1to 4 carbon atoms, respectively. Preference is given to a straight-chainor branched alkyl radical having 1 to 4 carbon atoms. The following maybe mentioned by way of example and by way of preference: methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,2-pentyl, 3-pentyl, neopentyl, n-hexyl, 2-hexyl and 3-hexyl.

In the context of the invention, (C₁-C₄)-alkylcarbonyl represents astraight-chain or branched alkyl radical having 1 to 4 carbon atomswhich is attached to the remainder of the molecule via a carbonyl group[—C(═O)—]. The following may be mentioned by way of example and by wayof preference: acetyl, propionyl, n-butyryl, isobutyryl, n-pentanoyl andpivaloyl.

In the context of the invention, (C₂-C₆)-alkenyl represents astraight-chain or branched alkenyl radical having 2 to 6 carbon atomsand a double bond. Preference is given to a straight-chain or branchedalkenyl radical having 3 to 6 carbon atoms. The following may bementioned by way of example and by way of preference: vinyl,n-prop-1-en-1-yl, allyl, isopropenyl, 2-methyl-2-propen-1-yl,n-but-1-en-1-yl, n-but-2-en-1-yl, n-but-3-en-1-yl, n-pent-2-en-1-yl,n-pent-3-en-1-yl, n-pent-4-en-1-yl, 3-methylbut-2-en-1-yl and4-methylpent-3-en-1-yl.

In the context of the invention, (C₂-C₆)-alkynyl represents astraight-chain or branched alkynyl radical having 2 to 6 carbon atomsand a triple bond. Preference is given to a straight-chain or branchedalkynyl radical having 3 to 6 carbon atoms. The following may bementioned by way of example and by way of preference: ethynyl,n-prop-1-yn-1-yl, n-prop-2-yn-1-yl, n-but-2-yn-1-yl, n-but-3-yn-1-yl,n-pent-2-yn-1-yl, n-pent-3-yn-1-yl and n-pent-4-yn-1-yl.

In the context of the invention, (C₁-C₄)-alkoxy represents astraight-chain or branched alkoxy radical having 1 to 4 carbon atoms.The following may be mentioned by way of example and by way ofpreference: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy,sec-butoxy and tert-butoxy.

In the context of the invention, (C₁-C₄)-alkoxymethyl represents astraight-chain or branched alkoxy radical having 1 to 4 carbon atomswhich is attached to the remainder of the molecule via a methylene group[—CH₂—] attached to the oxygen atom. The following may be mentioned byway of example and by way of preference: methoxymethyl, ethoxymethyl,n-propoxymethyl, iso-propoxymethyl, n-butoxymethyl andtert-butoxymethyl.

In the context of the invention, (C₁-C₄)-alkoxycarbonyl represents astraight-chain or branched alkoxy radical having 1 to 4 carbon atomswhich is attached to the remainder of the molecule via a carbonyl group[—C(═O)—] attached to the oxygen atom. The following may be mentioned byway of example and by way of preference: methoxycarbonyl,ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyland tert-butoxycarbonyl.

In the context of the invention, mono-(C₁-C₄)-alkylamino represents anamino group having a straight-chain or branched alkyl substituent having1 to 4 carbon atoms. The following may be mentioned by way of exampleand by way of preference: methylamino, ethylamino, n-propylamino,isopropylamino, n-butylamino and tert-butylamino.

In the context of the invention, di-(C₁-C₄)-alkylamino represents anamino group having two identical or different straight-chain or branchedalkyl substituents each having 1 to 4 carbon atoms. The following may bementioned by way of example and by way of preference: N,N-dimethylamino,N,N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-n-propylamino,N-isopropyl-N-methylamino, N-isopropyl-N-n-propylamino,N,N-diisopropylamino, N-n-butyl-N-methylamino, N,N-di-n-butylamino andN-tert-butyl-N-methylamino.

In the context of the invention, mono- and di-(C₁-C₄)-alkylaminocarbonylrepresent amino groups which are attached to the remainder of themolecule via a carbonyl group [—C(═O)—] and which have, respectively,one straight-chain or branched and two identical or differentstraight-chain or branched N-alkyl substituents each having 1 to 4carbon atoms. The following may be mentioned by way of example and byway of preference: methylaminocarbonyl, ethylaminocarbonyl,n-propylaminocarbonyl, isopropylaminocarbonyl, n-butylaminocarbonyl,tert-butylaminocarbonyl, N,N-dimethylaminocarbonyl,N,N-diethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl,N-methyl-N-n-propylaminocarbonyl, N,N-diisopropylaminocarbonyl,N-n-butyl-N-methylaminocarbonyl and N-tert-butyl-N-methylaminocarbonyl.

In the context of the invention, (C₁-C₄)-alkylcarbonylamino representsan amino group having a straight-chain or branched alkylcarbonylsubstituent which has 1 to 4 carbon atoms in the alkyl radical and isattached to the nitrogen atom via the carbonyl group. The following maybe mentioned by way of example and by way of preference: acetylamino,propionylamino, n-butyrylamino, isobutyrylamino, n-pentanoylamino andpivaloylamino.

In the context of the invention, (C₃-C₇)-cycloalkyl and(C₃-C₆)-cycloalkyl represent monocyclic, saturated cycloalkyl groupshaving 3 to 7 and 3 to 6 carbon atoms, respectively. Preference is givento a cycloalkyl radical having 3 to 6 carbon atoms. The following may bementioned by way of example and by way of preference: cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

5-membered heteroaryl in the definition of ring Q represents an aromaticheterocycle (heteroaromatic) which has a total of 5 ring atoms and whichcontains up to three identical or different ring heteroatoms from thegroup consisting of N, O and S and is attached via carbon ring atoms oroptionally a nitrogen ring atom. The following may be mentioned by wayof example: furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl,1,2-oxazolyl (isoxazolyl), 1,3-oxazolyl, 1,2-thiazolyl (isothiazolyl),1,3-thiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,4-oxadiazolyl,1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl and 1,3,4-thiadiazolyl.

6-membered heteroaryl in the definition of ring Q represents an aromaticheterocycle (heteroaromatic) having a total of 6 ring atoms and whichcontains one, two or three nitrogen ring atoms and is attached viacarbon ring atoms. The following may be mentioned by way of example:pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,4-triazinyl and1,3,5-triazinyl. Preference is given to 6-membered heteroaryl having oneor two nitrogen ring atoms such as pyridyl, pyrimidinyl, pyridazinyl andpyrazinyl.

In the context of the invention, 5- to 10-membered heteroaryl representsa mono- or optionally bicyclic aromatic heterocycle (heteroaromatic)which has a total of 5 to 10 ring atoms, which contains up to three ringheteroatoms from the group consisting of N, O and S and which isattached via a carbon ring atom or optionally a nitrogen ring atom. Thefollowing may be mentioned by way of example: furyl, pyrrolyl, thienyl,pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl,triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl,pyrazinyl, triazinyl, benzofuranyl, benzothienyl, benzimidazolyl,benzoxazolyl, benzothiazolyl, benzo-triazolyl, indolyl, indazolyl,quinolinyl, isoquinolinyl, naphthyridinyl, quinazolinyl, quinoxalinyl,phthalazinyl, pyrazolo[3,4-b]pyridinyl. Preference is given to mono- oroptionally bicyclic 5- to 10-membered heteroaryl radicals having up totwo heteroatoms from the group consisting of N, O and S. Particularpreference is given to monocyclic 5- or 6-membered heteroaryl radicalshaving up to two heteroatoms from the group consisting of N, O and S,such as, for example, furyl, thienyl, thiazolyl, oxazolyl, isothiazolyl,isoxazolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl,pyrazinyl.

In the context of the invention, halogen includes fluorine, chlorine,bromine and iodine. Preference is given to chlorine, fluorine orbromine, particularly preferably fluorine or chlorine.

In the context of the invention, an oxo substituent represents an oxygenatom which is attached to a carbon atom via a double bond.

In the context of the present invention, all radicals which occur morethan once are defined independently of one another. If radicals in thecompounds according to the invention are substituted, the radicals maybe mono- or polysubstituted, unless specified otherwise. Substitution byone or by two or three identical or different substituents is preferred.Particular preference is given to substitution by one or two identicalor different substituents. Very particular preference is given tosubstitution by one substituent.

In the context of the present invention, preference is given tocompounds of the formula (I) in which

-   R¹ represents (C₁-C₆)-alkyl which may be mono- to trisubstituted by    identical or different radicals selected from the group consisting    of fluorine, trifluoromethyl, oxo, hydroxyl, methoxy, ethoxy,    (C₃-C₆)-cycloalkyl and phenyl,    -   where (C₃-C₆)-cycloalkyl may be substituted up to two times by        identical or different radicals selected from the group        consisting of fluorine, methyl, trifluoromethyl, ethyl and        hydroxyl    -   and    -   where phenyl may be substituted up to two times by identical or        different radicals selected from the group consisting of        fluorine, chlorine, cyano, methyl, difluoromethyl,        trifluoromethyl, ethyl, hydroxyl, methoxy, trifluoromethoxy,        ethoxy, hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl and        aminocarbonyl,-    or-    represents (C₂-C₆)-alkenyl-    or-    represents (C₃-C₆)-cycloalkyl which may be mono- or disubstituted    by identical or different radicals selected from the group    consisting of fluorine, methyl, trifluoromethyl, ethyl and hydroxyl,-   Ar¹ represents phenyl or thienyl, each of which may be mono- or    disubstituted by identical or different radicals selected from the    group consisting of fluorine, chlorine, cyano, methyl,    trifluoromethyl, ethyl, hydroxyl, methoxy, trifluoromethoxy and    ethoxy,-   L¹ represents the group —CH₂— or —SO₂—,-   Q represents a phenyl ring, a 5-membered heteroaryl ring having up    to three ring heteroatoms from the group consisting of N, O and S or    a 6-membered heteroaryl ring having up to two nitrogen ring atoms,-   R² represents a substituent selected from the group consisting of    fluorine, chlorine, bromine, (C₁-C₄)-alkyl, (C₃-C₆)-cycloalkyl,    phenyl, (C₁-C₄)-alkoxy, hydroxycarbonyl, (C₁-C₄)-alkoxycarbonyl,    aminocarbonyl and mono-(C₁-C₄)-alkylaminocarbonyl,    -   where the (C₁-C₄)-alkyl substituent for its part may be        substituted by hydroxyl, (C₁-C₄)-alkoxy, carbamoyloxy,        hydroxycarbonyl, (C₁-C₄)-alkoxycarbonyl or aminocarbonyl or up        to three times by fluorine    -   and    -   where the phenyl substituent for its part may be substituted by        fluorine, chlorine, methyl or trifluoromethyl,-   n represents the number 0 or 1,-   L² represents a bond or represents a group of the formula    —(CR^(3A)R^(3B))_(p)— in which    -   R^(3A) represents hydrogen or methyl,    -   R^(3B) represents hydrogen, (C₁-C₄)-alkyl, hydroxycarbonyl,        (C₁-C₄)-alkoxycarbonyl or aminocarbonyl,        -   where (C₁-C₄)-alkyl may be substituted by hydroxyl or            carbamoyloxy,    -   and    -   p represents the number 1 or 2,        -   where in the case that the group —CR^(3A)R^(3B)— occurs            twice the individual meanings of R^(3A) and R^(3B) may in            each case be identical or different,-   and-   Ar² represents phenyl which may be mono- or disubstituted by    identical or different radicals selected from the group consisting    of fluorine, chlorine, cyano, difluoromethyl, trifluoromethyl,    (C₁-C₄)-alkyl, methoxy, difluoromethoxy, trifluoromethoxy and    ethoxy,    and salts, solvates and solvates of the salts thereof.

A particular embodiment of the present invention comprises compounds ofthe formula (I) in which

-   R¹ represents (C₁-C₄)-alkyl which may be mono- or disubstituted by    identical or different radicals selected from the group consisting    of fluorine, trifluoromethyl, oxo and hydroxyl, or represents allyl    or cyclopropyl,    and salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention comprisescompounds of the formula (I) in which

-   Ar¹ represents phenyl or thienyl, each of which is substituted by a    radical selected from the group consisting of fluorine, chlorine,    cyano, methyl, trifluoromethyl, ethyl, hydroxyl, methoxy,    trifluoromethoxy and ethoxy,    and salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention comprisescompounds of the formula (I) in which

-   Ar² represents phenyl which is mono- or disubstituted by identical    or different radicals selected from the group consisting of    fluorine, chlorine, cyano, difluoromethyl, trifluoromethyl,    (C₁-C₄)-alkyl, methoxy, difluoromethoxy, trifluoromethoxy and    ethoxy,    and salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention comprisescompounds of the formula (I) in which

-   Q represents an optionally substituted phenyl ring of the formula

-   -   in which    -   * denotes the point of attachment to the group L¹    -   and    -   ** denotes the point of attachment to the group L²,    -   and    -   R^(2A) represents hydrogen, fluorine, chlorine, bromine, methyl,        trifluoromethyl, hydroxymethyl, carbamoyloxymethyl,        hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl,        methylaminocarbonyl or tert-butylaminocarbonyl,        and salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention comprisescompounds of the formula (I) in which

-   Q represents a pyridyl ring or pyrimidinyl ring of the formula

-   -   in which    -   * denotes the point of attachment to the group L¹    -   and    -   ** denotes the point of attachment to the group L²,        and salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention comprisescompounds of the formula (I) in which

-   Q represents an optionally substituted 5-membered heteroaryl ring of    the formula

-   -   in which    -   * denotes the point of attachment to the group L¹    -   and    -   ** denotes the point of attachment to the group L²,    -   R^(2B) represents hydrogen, methyl or trifluoromethyl    -   and    -   R^(2C) represents hydrogen or methyl which may be substituted by        hydroxycarbonyl, methoxycarbonyl or aminocarbonyl,        and salts, solvates and solvates of the salts thereof.

Particular preference in the context of the present invention is givento compounds of the formula (I) in which

-   R¹ represents (C₁-C₄)-alkyl which may be mono- or disubstituted by    identical or different radicals selected from the group consisting    of fluorine, trifluoromethyl, oxo, hydroxyl and phenyl,    -   where phenyl for its part may be substituted by a radical        selected from the group consisting of fluorine, chlorine,        methyl, trifluoromethyl, methoxy, hydroxycarbonyl and        methoxycarbonyl,-    or-    represents allyl or cyclopropyl,-   Ar¹ represents phenyl or thienyl, each of which is substituted by a    radical selected from the group consisting of fluorine and chlorine,-   L¹ represents the group —CH₂—,-   Q represents a pyridyl ring, a pyrimidinyl ring or an optionally    substituted phenyl ring of the formula

-   -   or    -   represents an optionally substituted 5-membered heteroaryl ring        of the formula

-   -   in which    -   * denotes the point of attachment to the group L¹    -   and    -   ** denotes the point of attachment to the group L²,    -   R^(2A) represents hydrogen, fluorine, chlorine, bromine, methyl,        trifluoromethyl, hydroxymethyl, carbamoyloxymethyl,        hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl,        methylaminocarbonyl or tert-butylaminocarbonyl,    -   R^(2B) represents hydrogen, methyl or trifluoromethyl    -   and    -   R^(2C) represents hydrogen or methyl which may be substituted by        hydroxycarbonyl, methoxycarbonyl or aminocarbonyl,

-   L² represents a bond or the group —CH₂—

-   and

-   Ar² represents phenyl which is mono- or disubstituted by identical    or different radicals selected from the group consisting of    fluorine, chlorine, methyl, trifluoromethyl, methoxy and    trifluoromethoxy,    and salts, solvates and solvates of the salts thereof.

Very particular preference in the context of the present invention isgiven to compounds of the formula (I) in which

-   R¹ represents (C₁-C₄)-alkyl which may be mono- or disubstituted by    identical or different radicals selected from the group consisting    of fluorine, trifluoromethyl and hydroxyl, or represents    cyclopropyl,-   Ar¹ represents p-chlorophenyl,-   L¹ represents the group —CH₂—,-   Q represents a pyrimidinyl ring of the formula

-   -   or    -   represents an optionally substituted 5-membered heteroaryl ring        of the formula

-   -   in which    -   * denotes the point of attachment to the group L¹    -   and    -   ** denotes the point of attachment to the group L²,    -   R^(2B) represents hydrogen, methyl or trifluoromethyl    -   and    -   R^(2C) represents hydrogen or methyl which may be substituted by        hydroxycarbonyl, methoxycarbonyl or aminocarbonyl,

-   L² represents a bond or the group —CH₂—

-   and

-   Ar² represents phenyl which is mono- or disubstituted by identical    or different radicals selected from the group consisting of    fluorine, chlorine, methyl, trifluoromethyl, methoxy and    trifluoromethoxy,    and salts, solvates and solvates of the salts thereof.

The definitions of radicals indicated specifically in the respectivecombinations or preferred combinations of radicals are replaced asdesired irrespective of the particular combinations indicated for theradicals also by definitions of radicals of other combinations.Combinations of two or more of the abovementioned preferred ranges arevery particularly preferred.

The invention furthermore provides a process for preparing the compoundsof the formula (I) according to the invention, characterized in that a5-aryl-1,2,4-triazolone derivative of the formula (H)

in which Ar¹ and R¹ have the meanings given above,is reacted in the presence of a base either

-   [A] with a compound of the formula (III)

-   -   in which Ar², L¹, L², Q, R² and n have the meanings given above    -   and    -   X¹ represents a leaving group such as chlorine, bromine, iodine,        mesylate or tosylate,    -   to give a compound of the formula (I)

-   or

-   [B] in an alternative in the case that L² in formula (I) represents    a bond and the group Ar² is attached to a carbon atom of ring Q    -   with a compound of the formula (IV)

-   -   in which L¹, Q, R² and n have the meanings given above,    -   X¹ represents a leaving group such as chlorine, bromine, iodine,        mesylate or tosylate    -   and    -   X² represents a leaving group, such as chlorine, bromine,        iodine, mesylate or triflate, which is attached to a carbon atom        of ring Q,    -   to give an intermediate of the formula (V)

-   -   in which Ar¹, L¹, Q, R¹, R², X² and n have the meanings given        above,    -   and this is then coupled in the presence of a suitable        transition metal catalyst with a compound of the formula (VI)

Ar²-M  (VI),

-   -   in which Ar² has the meaning given above    -   and    -   M represents a group of the formula —B(OR⁴)₂, —MgHal, —ZnHal or        —Sn(R⁵)₃ in which        -   Hal represents halogen, in particular chlorine, bromine or            iodine,        -   R⁴ represents hydrogen or (C₁-C₄)-alkyl or both radicals R⁴            are attached to one another and together form a —(CH₂)₂—,            —(CH₂)₃—, —C(CH₃)₂—C(CH₃)₂— or —CH₂—C(CH₃)₂—CH₂— bridge        -   and        -   R⁵ represents (C₁-C₄)-alkyl,    -   to give a compound of the formula (I-A)

-   -   in which Ar¹, Ar², L¹, Q, R¹, R² and n have the meanings given        above,

-   or

-   [C] in an alternative in the case that L² in formula (I) represents    the group —(CR^(3A)R^(3B))_(p)—, as defined above, and is attached    to a nitrogen atom of ring Q,    -   with a compound of the formula (VII)

-   -   in which L¹, R² and n have the meanings given above,    -   Q′ represents a 5-membered heteroaryl ring, as defined above        under Q, which contains a trivalent nitrogen ring atom attached        to the hydrogen atom indicated,    -   and    -   X¹ represents a leaving group such as chlorine, bromine, iodine,        mesylate or tosylate, to give an intermediate of the formula        (VIII)

-   -   in which Ar¹, L¹, Q′, R¹, R² and n have the meanings given        above,    -   and this is then N-alkylated in the presence of a base with a        compound of the formula (IX)

-   -   in which Ar² has the meaning given above,    -   L^(2A) represents the group —(CR^(3A)R^(3B))_(p)—, as defined        above,    -   and    -   X³ represents a leaving group such as chlorine, bromine, iodine,        mesylate or tosylate,    -   to give a compound of the formula (I-B)

-   -   in which Ar¹, Ar², L¹, L^(2A), Q′, R¹, R² and n have the        meanings given above,        and the resulting compounds of the formula (I), (I-A) or (I-B)        are optionally separated into their enantiomers and/or        diastereomers and/or converted with the appropriate (i) solvents        and/or (ii) bases or acids into their solvates, salts and/or        solvates of the salts.

Inert solvents for the process steps (II)+(III)→(I), (II)+(IV)→(V),(II)+(VII)→(VIII) and (VIII)+(IX)→(I-B) are, for example, halogenatedhydrocarbons such as dichloromethane, trichloromethane, carbontetrachloride, trichloroethylene or chlorobenzene, ethers such asdiethyl ether, diisopropyl ether, methyl tert-butyl ether,tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane orbis-(2-methoxyethyl) ether, hydrocarbons such as benzene, toluene,xylene, pentane, hexane, cyclohexane or mineral oil fractions, ordipolar aprotic solvents such as acetone, methyl ethyl ketone, ethylacetate, acetonitrile, N,N-dimethylformamide (DMF),N,N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO),N,N′-dimethylpropyleneurea (DMPU), N-methylpyrrolidinone (NMP) orpyridine. It is also possible to use mixtures of the solvents mentioned.Preference is given to using tetrahydrofuran, acetonitrile, acetone ordimethylformamide.

Suitable bases for process steps (II)+(III)→(I), (H)+(IV)→(V),(II)+(VII)→(VIII) and (VIII)+(IX)→(I-B) are the customary inorganic ororganic bases. These preferably include alkali metal hydroxides such as,for example, lithium hydroxide, sodium hydroxide or potassium hydroxide,alkali metal or alkaline earth metal carbonates such as lithiumcarbonate, sodium carbonate, potassium carbonate, calcium carbonate orcesium carbonate, alkali metal alkoxides such as sodium methoxide orpotassium methoxide, sodium ethoxide or potassium ethoxide or sodiumtert-butoxide or potassium tert-butoxide, alkali metal hydrides such assodium hydride or potassium hydride, amides such as sodium amide,lithium bis(trimethylsilyl)amide or potassium bis(trimethylsilyl)amideor lithium diisopropylamide, or organic amines such as triethylamine,N-methylmorpholine, N-methylpiperidine, N,N-diisopropylethylamine,pyridine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN),1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or1,4-diazabicyclo[2.2.2]octane (DABCO®). Preference is given to usingpotassium carbonate or cesium carbonate or sodium hydride.

Here, the base is employed in an amount of from 1 to 5 mol, preferablyin an amount of from 1 to 2.5 mol, based on 1 mole of the compound ofthe formula (II) or (VIII). These process steps may optionally becarried out in an advantageous manner with addition of alkylationcatalysts such as, for example, lithium bromide, sodium iodide,tetra-n-butylammonium bromide or benzyltriethyl-ammonium chloride. Thereactions are generally carried out in a temperature range of from −20°C. to +150° C., preferably at from 0° C. to +80° C. The reactions can becarried out at atmospheric, at elevated or at reduced pressure (forexample at from 0.5 to 5 bar); in general, the reactions are carried outat atmospheric pressure.

Suitable inert solvents for the process step (V)+(VI)→(I-A) are, forexample, aromatic hydrocarbons such as benzene, toluene or xylene,ethers such as diethyl ether, diisopropyl ether, methyl tert-butylether, 1,2-dimethoxyethane, bis-(2-methoxyethyl) ether, tetrahydrofuranor 1,4-dioxane, or dipolar aprotic solvents such as acetonitrile,N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), dimethylsulfoxide (DMSO), N,N′-dimethylpropyleneurea (DMPU),N-methylpyrrolidinone (NMP) or pyridine. It is also possible to usemixtures of the solvents mentioned. Preference is given to usingtoluene, tetrahydrofuran, 1,4-dioxane or dimethylformamide.

The coupling reaction (V)+(VI)→(I-A) is generally carried out with theaid of a transition metal catalyst. Suitable for this purpose are coppercatalysts such as, for example, copper(I) iodide, and in particularpalladium catalysts such as, for example, palladium on activated carbon,palladium(II) acetate, bis(triphenylphosphino)palladium(II) chloride,bis(acetonitrile)palladium(II) chloride,[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride,bis(dibenzylideneacetone)palladium(0),tris(dibenzylideneacetone)dipalladium(0) ortetrakis(triphenylphosphino)palladium(0), optionally in combination withadditional phosphane ligands such as tri-tert-butylphosphine,2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl,dicyclohexyl[2′,4′,6′-tris(1-methylethyl)-biphenyl-2-yl]phosphane(XPHOS) or 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (xantphos)[cf., for example, J. Hassan et al., Chem. Rev. 102, 1359-1469 (2002);V. Farina, V. Krishnamurthy and W. J. Scott, in: The Stille Reaction,Wiley, New York, 1998].

Coupling with an aryl boronate [M=B(OR⁴)₂; “Suzuki coupling”] isgenerally carried out with addition of an inorganic base. Suitable forthis purpose are in particular alkali metal carbonates, bicarbonates,phosphates, hydrogenphosphates, acetates or fluorides such as sodiumcarbonate, potassium carbonate, sodium bicarbonate, potassiumbicarbonate, tripotassium phosphate, disodium hydrogenphosphate,dipotassium hydrogenphosphate, sodium acetate, potassium acetate,potassium fluoride and cesium fluoride. Such bases can also be employedin the form of their aqueous solutions. Preference is given to usingsodium carbonate or potassium carbonate or tripotassium phosphate.

The process step (V)+(VI)→(I-A) is generally carried out in atemperature range of from +20° C. to +200° C., preferably at from +60°C. to +150° C., at atmospheric pressure. However, it is also possible tocarry out the reaction at reduced or at elevated pressure (for exampleat from 0.5 to 5 bar). It may optionally be advantageous to carry outthe reaction with microwave irradiation.

In a particular variant of the process [A] described above, compounds ofthe formula (I) according to the invention may optionally also beprepared by initially reacting, instead of the compound (II), atemporarily protected 1,2,4-triazolone derivative of the formula (X)

in which Ar¹ has the meaning given aboveandPG represents a suitable protective group such as, for example, allyl orp-methoxybenzyl,with a compound of the formula (III); the resulting product of theformula (XI)

in which Ar¹, Ar², L¹, L², PG, Q, R² and n have the meanings givenabove,can then, after removal of the protective group, which gives thecompound of the formula (XII)

in which Ar¹, Ar², L¹, L², Q, R² and n have the meanings given above,be converted by base-induced reaction with a compound of the formula(XIII)

R¹—X⁴  (XIII),

in which R¹ has the meaning given aboveandX⁴ represents a leaving group such as chlorine, bromine, iodine,mesylate or tosylate,into corresponding compounds of the formula (I).

An analogous transformation PG→R¹ can optionally also take place duringthe process variants [B] and [C] described above, in each case startingwith the protected aryltriazolone (X).

Some of the compounds of the formula (XI) which are PG-protected in thismanner also have significant vasopressin-antagonistic activity and aretherefore also included in the scope of the present invention, i.e. thecompounds of the formula (I).

Introduction and removal of the protective group PG is carried out bycustomary methods known from the literature [see, for example, T. W.Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, Wiley,New York, 1999]. Thus, the allyl group is preferably removed with theaid of formic acid in the presence of thetetrakis(triphenylphosphine)palladium(0) catalyst and an amine base suchas triethylamine. The removal of the p-methoxybenzyl protective group ispreferably carried out with the aid of strong acids such as, forexample, trifluoroacetic acid, or oxidatively, for example by treatmentwith 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) or ammoniumcerium(IV) nitrate.

The subsequent reaction (XII)+(XIII)→(I) is carried out analogously tothe process step (II)+(III)→(I) described above. Here, preferred inertsolvents are acetone, acetonitrile, dimethylformamide, dimethylsulfoxide, toluene, tetrahydrofuran, glycol dimethyl ether and mixturesthereof. Preferred for use as base is sodium hydride or potassiumcarbonate or cesium carbonate. The reaction is generally carried out atatmospheric pressure in a temperature range of from 0° C. to +150° C.,preferably at from +20° C. to +80° C.

The 1,2,4-triazolone derivatives of the formula (II) can be preparedstarting with carbohydrazides of the formula (XIV) by reaction withisocyanates of the formula (XV) or nitrophenyl carbamates of the formula(XVI) and subsequent base-induced cyclization of thehydrazinecarboxamide intermediates (XVII) (see Scheme 1):

In an analogous manner, it is also possible to obtain temporarilyprotected 1,2,4-triazolone derivatives of the formula (X), in particularthose in which PG represents allyl or p-methoxybenzyl.

Compounds of the formula (III) in which L¹ represents —CH₂— and L²represents a bond can be prepared, for example, analogously to theprocess [B] described above by transition metal-catalyzed coupling ofthe compound of the formula (VI) with a compound of the formula (XVIII)and subsequent free-radical halogenation of the intermediate (XIX)(Scheme 2):

In a variant of this process, coupling is carried out with an esterderivative of the formula (XX); the subsequent reduction to the primaryalcohol of the formula (XXII) and customary conversion, in accordancewith the literature, of the hydroxyl function into a leaving group givesthe corresponding compound of the formula (III-B) (Scheme 3):

In a similar manner, it is possible to prepare compounds of the formula(III) in which L¹ represents —CH₂— and L² represents the group—(CR^(3A)R^(3B))_(p)—, which is attached to a nitrogen atom of ring Qfrom corresponding carboxylic esters of the formula (XXIV) which fortheir part can be obtained analogously to the process [C] describedabove (see Scheme 4):

Compounds of the formula (I) according to the invention in which ring Qrepresents a 5-membered heteroaryl ring can optionally also be preparedsimilarly to methods known from the literature via a de novo synthesisof the heteroaryl system in question. Such process routes can beillustrated in an exemplary manner by Reaction Schemes 5-10 below:

Further compounds of the formula (I) according to the invention can, ifexpedient, also be prepared by conversion of functional groups ofindividual radicals and substituents, in particular those listed underR¹, R², Ar¹ and Ar², starting with other compounds of the formula (I)obtained by the above processes. These conversions are carried out bycustomary processes familiar to the person skilled in the art andinclude, for example, reactions such as nucleophilic or electrophilicsubstitution reactions, transition metal-mediated coupling reactions(for example the Suzuki or Heck reaction), oxidation, reduction,hydrogenation, alkylation, acylation, amination, hydroxylation,etherification, esterification, ether cleavage and hydrolysis, formationof nitriles, carboxamides, sulfonamides, carbamates and ureas, and theintroduction and removal of temporary protective groups [cf. also thepreparation of the Working Examples described in detail in theExperimental Part below].

The intermediates of the formula (XXXVI) can be prepared in a simplemanner by base-induced alkylation of the 5-aryl-1,2,4-triazol-3-ones ofthe formula (II) with haloacetic esters of the formula (XLVII); thecorresponding carboxylic acids of the formula (XXV) can be obtained bysubsequent ester hydrolysis (see Scheme 11):

Alternatively, the compounds of the formula (XXXVI) can also be preparedfrom N-(alkoxy-carbonyl)arylthioamides of the formula (XLIX), which areknown from the literature [see, for example, M. Arnswald, W. P. Neumann,J. Org. Chem. 58 (25), 7022-7028 (1993); E. P. Papadopoulos, J. Org.Chem. 41 (6), 962-965 (1976)], by reaction with hydrazinoacetic estersof the formula (XLVIII) and subsequent alkylation at N-4 of thetriazolone (L) (Scheme 12):

Separation of the compounds according to the invention into thecorresponding enantiomers and/or diastereomers can take place whereappropriate, depending on expediency, even at the stage of individualintermediates, as listed above, which are then reacted further inseparated form in accordance with the above-described process steps.Such a separation of the stereoisomers can be carried out byconventional methods known to the person skilled in the art. Preferenceis given to using chromatographic methods, in particular HPLCchromatography on an achiral or chiral phase.

The compounds of the formulae (IV), (VI), (VII), (IX), (XIII), (XIV),(XV), (XVI), (XVIII), (XX), (XXIII), (XXVI), (XXXI), (XXXIV), (XXXVIII),(XXXIX), (XLIII), (XLV), (XLVII), (XLVIII) and (XLIX) are eithercommercially available or described as such in the literature, or theycan be prepared in a manner obvious to the person skilled in the artanalogously to the methods published in the literature. Numerousdetailed procedures and literature references for preparing the startingmaterials can also be found in the Experimental Part in the section onthe preparation of the starting materials and intermediates.

The compounds according to the invention possess valuablepharmacological properties and can be used for the prevention and/ortreatment of various diseases and disease-induced states in humans andanimals.

The compounds according to the invention are potent selective V1a, V2 ordual V1a/V2 receptor antagonists, which inhibit vasopressin activity invitro and in vivo. In addition, the compounds according to the inventionare also suitable as antagonists at the related oxytocin receptor.

The compounds according to the invention are particularly suitable forthe prophylaxis and/or treatment of cardiovascular diseases. In thisconnection, the following may for example and preferably be mentioned astarget indications: acute and chronic heart failure, arterialhypertension, coronary heart disease, stable and unstable anginapectoris, myocardial ischemia, myocardial infarction, shock,arteriosclerosis, atrial and ventricular arrhythmias, transitory andischemic attacks, stroke, inflammatory cardiovascular diseases,peripheral and cardiac vascular diseases, peripheral circulationdisorders, arterial pulmonary hypertension, spasms of the coronaryarteries and peripheral arteries, thromboses, thromboembolic diseases,edema formation such as for example pulmonary edema, cerebral edema,renal edema or heart failure-related edema, and restenoses for exampleafter thrombolysis treatments, percutaneous-transluminal angioplasties(PTA), transluminal coronary angioplasties (PTCA), heart transplants andbypass operations.

In the sense of the present invention, the term heart failure alsoincludes more specific or related disease forms such as right heartfailure, left heart failure, global insufficiency, ischemiccardiomyopathy, dilatative cardiomyopathy, congenital heart defects,heart valve defects, heart failure with heart valve defects, mitralvalve stenosis, mitral valve insufficiency, aortic valve stenosis,aortic valve insufficiency, tricuspidal stenosis, tricuspidalinsufficiency, pulmonary valve stenosis, pulmonary valve insufficiency,combined heart valve defects, heart muscle inflammation (myocarditis),chronic myocarditis, acute myocarditis, viral myocarditis, diabeticheart failure, alcohol-toxic cardiomyopathy, cardiac storage diseases,diastolic heart failure and systolic heart failure.

Furthermore, the compounds according to the invention are suitable foruse as a diuretic for the treatment of edemas and in electrolytedisorders, in particular in hypervolemic and euvolemic hyponatremia.

The compounds according to the invention are also suitable for theprophylaxis and/or treatment of polycystic kidney disease (PCKD) and thesyndrome of inadequate ADH secretion (SIADH).

In addition, the compounds according to the invention can be used forthe prophylaxis and/or treatment of liver cirrhosis, ascites, diabetesmellitus and diabetic complications such as for example neuropathy andnephropathy, acute and chronic kidney failure and chronic renalinsufficiency.

Further, the compounds according to the invention are suitable for theprophylaxis and/or treatment of central nervous disorders such asanxiety states and depression, of glaucoma and of cancer, in particularof pulmonary tumors.

Furthermore, the compounds according to the invention can be used forthe prophylaxis and/or treatment of inflammatory diseases, asthmaticdiseases, chronic-obstructive respiratory tract diseases (COPD), painconditions, prostatic hypertrophy, incontinence, bladder inflammation,hyperactive bladder, diseases of the adrenals such as for examplepheochromocytoma and adrenal apoplexy, diseases of the intestine such asfor example Crohn's disease and diarrhea, or of menstrual disorders suchas for example dysmenorrhea or of endometriosis.

By virtue of their activity profile, the compounds according to theinvention are particularly suitable for the treatment and/or prophylaxisof acute and chronic heart failure, hypervolemic and euvolemichyponatremia, liver cirrhosis, ascites, edemas, and the syndrome ofinadequate ADH secretion (SIADH).

A further object of the present invention is the use of the compoundsaccording to the invention for the treatment and/or prophylaxis ofdiseases, in particular of the diseases mentioned above.

A further object of the present invention is the use of the compoundsaccording to the invention for the production of a medicament for thetreatment and/or prophylaxis of diseases, in particular of the diseasesmentioned above.

A further object of the present invention is the use of the compoundsaccording to the invention in a method for the treatment and/orprophylaxis of diseases, in particular of the diseases mentioned above.

A further object of the present invention is a method for the treatmentand/or prophylaxis of diseases, in particular of the diseases mentionedabove, with the use of an effective quantity of at least one of thecompounds according to the invention.

The compounds according to the invention can be used alone or ifnecessary in combination with other active substances. A further objectof the present invention are medicaments which contain at least one ofthe compounds according to the invention and one or more other activesubstances, in particular for the treatment and/or prophylaxis of thediseases mentioned above. As combination active substances suitable forthis, the following may for example and preferably be mentioned:

-   -   organic nitrates and NO donors, such as for example sodium        nitroprusside, nitroglycerine, isosorbide mononitrate,        isosorbide dinitrate, molsidomine or SIN-1, and inhalational NO;    -   diuretics, in particular loop diuretics and thiazides and        thiazide-like diuretics;    -   positive-isotropically active compounds, such as for example        cardiac glycosides (digoxin), and beta-adrenergic and        dopaminergic agonists such as isoproterenol, adrenalin,        noradrenalin, dopamine and dobutamine;    -   compounds which inhibit the degradation of cyclic guanosine        monophosphate (cGMP) and/or cyclic adenosine monophosphate        (cAMP), such as for example inhibitors of phosphodiesterases        (PDE) 1, 2, 3, 4 and/or 5, in particular PDE 5 inhibitors such        as sildenafil, vardenafil and tadalafil, and PDE 3 inhibitors        such as amrinone and milrinone;    -   natriuretic peptides such as for example “atrial natriuretic        peptide” (ANP, anaritide), “B-type natriuretic peptide” or        “brain natriuretic peptide” (BNP, nesiritide), “C-type        natriuretic peptide” (CNP) and urodilatin;    -   calcium sensitizers, such as for example and preferably        levosimendan;    -   NO- and heme-independent activators of guanylate cyclase, such        as in particular cinaciguat and also the compounds described in        WO 01/19355, WO 01/19776, WO 01/19778, WO 01/19780, WO 02/070462        and WO 02/070510;    -   NO-independent, but heme-dependent stimulators of guanylate        cyclase, such as in particular riociguat and also the compounds        described in WO 00/06568, WO 00/06569, WO 02/42301 and WO        03/095451;    -   inhibitors of human neutrophil elastase (HNE), such as for        example sivelestat or DX-890 (reltran);    -   compounds inhibiting the signal transduction cascade, such as        for example tyrosine kinase inhibitors, in particular sorafenib,        imatinib, gefitinib and erlotinib;    -   compounds influencing the energy metabolism of the heart, such        as for example and preferably etomoxir, dichloroacetate,        ranolazine or trimetazidine;    -   agents with antithrombotic action, for example and preferably        from the group of the thrombocyte aggregation inhibitors,        anticoagulants or profibrinolytic substances;    -   blood pressure-lowering active substances, for example and        preferably from the group of the calcium antagonists,        angiotensin AII antagonists, ACE inhibitors, vasopeptidase        inhibitors, inhibitors of neutral endopeptidase, endothelin        antagonists, renin inhibitors, alpha-receptor blockers,        beta-receptor blockers, mineralocorticoid receptor antagonists        and rho-kinase inhibitors; and/or    -   active substances modifying the fat metabolism, for example and        preferably from the group of the thyroid receptor agonists,        cholesterol synthesis inhibitors such as for example and        preferably HMG-CoA reductase or squalene synthesis inhibitors,        ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR-alpha,        PPAR-gamma and/or PPAR-delta agonists, cholesterol absorption        inhibitors, lipase inhibitors, polymeric gallic acid adsorbers,        gallic acid reabsorption inhibitors and lipoprotein(a)        antagonists.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a diuretic, such asfor example and preferably furosemide, bumetanide, torsemide,bendroflumethiazide, chlorothiazide, hydrochlorothiazide,hydroflumethiazide, methyclothiazide, polythiazide, trichloromethiazide,chlorothalidone, indapamide, metolazone, quinethazone, acetazolamide,dichlorophenamide, methazolamide, glycerine, isosorbide, mannitol,amiloride or triamterene.

Agents with antithrombotic action are understood preferably to meancompounds from the group of the thrombocyte aggregation inhibitors,anticoagulants or profibrinolytic substances.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a thrombocyteaggregation inhibitor, such as for example and preferably aspirin,clopidogrel, ticlopidine or dipyridamole.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a thrombin inhibitor,such as for example and preferably ximelagatran, melagatran, dabigatran,bivalirudin or clexane.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a GPIIb/IIIaantagonist, such as for example and preferably tirofiban or abciximab.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a factor Xainhibitor, such as for example and preferably rivaroxaban, DU-176b,apixaban, otamixaban, fidexaban, razaxaban, fondaparinux, idraparinux,PMD-3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC906, JTV 803, SSR-126512 or SSR-128428.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with heparin or a lowmolecular weight (LMW) heparin derivative.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a vitamin Kantagonist, such as for example and preferably coumarin.

Blood pressure-lowering agents are understood preferably to meancompounds from the group of the calcium antagonists, angiotensin AIIantagonists, ACE inhibitors, vasopeptidase inhibitors, inhibitors ofneutral endopeptidase, endothelin antagonists, renin inhibitors,alpha-receptor blockers, beta-receptor blockers, mineralocorticoidreceptor antagonists, rho-kinase inhibitors and diuretics.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a calcium antagonist,such as for example and preferably nifedipine, amlodipine, verapamil ordiltiazem.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an angiotensin AIIantagonist, such as for example and preferably losartan, candesartan,valsartan, telmisartan or embusartan.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an ACE inhibitor,such as for example and preferably enalapril, captopril, lisinopril,ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a vasopeptidaseinhibitor or inhibitor of neutral endopeptidase (NEP), such as forexample and preferably omapatrilat or AVE-7688.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an endothelinantagonist, such as for example and preferably bosentan, darusentan,ambrisentan or sitaxsentan.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a renin inhibitor,such as for example and preferably aliskiren, SPP-600 or SPP-800.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an alpha-1 receptorblocker, such as for example and preferably prazosin.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a beta-receptorblocker, such as for example and preferably propranolol, atenolol,timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol,metipranolol, nadolol, mepindolol, carazalol, sotalol, metoprolol,betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol,carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucindolol.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a mineralocorticoidreceptor antagonist, such as for example and preferably spironolactone,eplerenone, canrenone or potassium canrenoate.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a rho-kinaseinhibitor, such as for example and preferably fasudil, Y-27632,SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095 or BA-1049.

Fat metabolism-modifying agents are understood preferably to meancompounds from the group of the CETP inhibitors, thyroid receptoragonists, cholesterol synthesis inhibitors such as HMG-CoA reductase orsqualene synthesis inhibitors, ACAT inhibitors, MTP inhibitors,PPAR-alpha, PPAR-gamma and/or PPAR-delta agonists, cholesterolabsorption inhibitors, polymeric gallic acid adsorbers, gallic acidreabsorption inhibitors, lipase inhibitors and lipoprotein(a)antagonists.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a CETP inhibitor,such as for example and preferably torcetrapib, dalcetrapib,anacetrapib, BAY 60-5521 or CETP-vaccine (CETi-1).

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a thyroid receptoragonist, such as for example and preferably D-thyroxine,3,5,3′-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an HMG-CoA reductaseinhibitor from the class of the statins, such as for example andpreferably lovastatin, simvastatin, pravastatin, fluvastatin,atorvastatin, rosuvastatin or pitavastatin.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a squalene synthesisinhibitor, such as for example and preferably BMS-188494 or TAK-475.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an ACAT inhibitor,such as for example and preferably avasimibe, melinamide, pactimibe,eflucimibe or SMP-797.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an MTP inhibitor,such as for example and preferably implitapide, BMS-201038, R-103757 orJTT-130.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a PPAR-gamma agonist,such as for example and preferably pio-glitazone or rosiglitazone.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a PPAR-delta agonist,such as for example and preferably GW-501516 or BAY 68-5042.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a cholesterolabsorption inhibitor, such as for example and preferably ezetimibe,tiqueside or pamaqueside.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a lipase inhibitor,such as for example and preferably orlistat.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a polymeric gallicacid adsorber, such as for example and preferably cholestyramine,colestipol, colesolvam, cholestagel or colestimide.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a gallic acidreabsorption inhibitor, such as for example and preferably ASBT (=IBAT)inhibitors such as for example AZD-7806, S-8921, AK-105, BARI-1741,SC-435 or SC-635.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a lipoprotein(a)antagonist, such as for example and preferably gemcabene calcium(CI-1027) or nicotinic acid.

A further object of the present invention are medicaments which containat least one compound according to the invention, usually together withone or more inert, non-toxic, pharmaceutically suitable auxiliaries, andthe use thereof for the aforesaid purposes.

The compounds according to the invention can act systemically and/orlocally. For this purpose, they can be administered in a suitablemanner, such as for example by the oral, parenteral, pulmonary, nasal,sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctivalor otic routes or as an implant or stent.

For these administration routes, the compounds according to theinvention can be administered in suitable administration forms.

For oral administration, administration forms which function accordingto the state of the art, releasing the compounds according to theinvention rapidly and/or in a modified manner, which contain thecompounds according to the invention in crystalline and/or amorphizedand/or dissolved form, such as for example tablets (uncoated or coatedtablets, for example with gastric juice-resistant or delayed dissolutionor insoluble coatings, which control the release of the compoundaccording to the invention), tablets rapidly disintegrating in the oralcavity or films/wafers, films/lyophilisates, capsules (for example hardor soft gelatine capsules), sugar-coated tablets, granules, pellets,powders, emulsions, suspensions, aerosols or solutions are suitable.

Parenteral administration can be effected by omitting an absorption step(e.g. intravenous, intra-arterial, intracardial, intraspinal orintralumbar administration) or by involving absorption (e.g.intra-muscular, subcutaneous, intracutaneous, percutaneous orintraperitoneal administration). Suitable administration forms forparenteral administration include injection and infusion preparations inthe form of solutions, suspensions, emulsions, lyophilisates or sterilepowders.

For the other administration routes, for example inhalation formulations(including powder inhalers and nebulizers), nasal drops, solutions orsprays, tablets for lingual, sublingual or buccal administration,tablets, films/wafers or capsules, suppositories, oral or ophthalmicpreparations, vaginal capsules, aqueous suspensions (lotions, shakablemixtures), lipophilic suspensions, ointments, creams, transdermaltherapeutic systems (e.g. plasters), milk, pastes, foams, dustingpowders, implants or stents are suitable.

Oral or parenteral administration, in particular oral and intravenousadministration, are preferred.

The compounds according to the invention can be converted into thestated administration forms. This can be effected in a manner known perse by mixing with inert, non-toxic, pharmaceutically suitableauxiliaries. These additives include carriers (for examplemicrocrystalline cellulose, lactose, mannitol), solvents (e.g. liquidpolyethylene glycols), emulsifiers and dispersants or wetting agents(for example sodium dodecylsulfate, polyoxysorbitan oleate), binders(for example polyvinylpyrrolidone), synthetic and natural polymers (forexample albumin), stabilizers (e.g. antioxidants such as for exampleascorbic acid), colorants (e.g. inorganic pigments such as for exampleiron oxides) and flavor and/or odor correctors.

In general, to achieve effective results in parenteral administration ithas been found advantageous to administer quantities of about 0.001 to10 mg/kg, preferably about 0.01 to 1 mg/kg body weight. In oraladministration, the dosage is about 0.01 bis 100 mg/kg, preferably about0.01 to 20 mg/kg and quite especially preferably 0.1 to 10 mg/kg bodyweight.

Nonetheless it can sometimes be necessary to deviate from saidquantities, namely depending on body weight, administration route,individual response to the active substance, nature of the preparationand time or interval at which the administration takes place. Thus insome cases it can be sufficient to manage with less than the aforesaidminimum quantity, while in other cases the stated upper limit must beexceeded. In the event of administration of larger quantities, it may beadvisable to divide these into several individual administrationsthroughout the day.

The following practical examples illustrate the invention. The inventionis not limited to the examples.

Unless otherwise stated, the percentages stated in the following testsand examples are percent by weight, parts are parts by weight, andsolvent ratios, dilution ratios and concentration information aboutliquid/liquid solutions are each based on volume.

EXAMPLES Abbreviations and Acronyms

-   Ac acetyl-   AIBN 2,2′-azobis-2-methylpropanenitrile-   Alk alkyl-   Boc tert-butoxycarbonyl-   Ex. Example-   CI chemical ionization (in MS)-   DCI direct chemical ionization (in MS)-   DME 1,2-dimethoxyethane-   DMF N,N-dimethylformamide-   DMSO dimethyl sulfoxide-   EDC N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride-   ee enantiomeric excess-   EA ethyl acetate-   eq. equivalent(s)-   ESI electrospray ionization (in MS)-   GC/MS gas chromatography-coupled mass spectrometry-   h hour(s)-   Hal halogen-   HOBt 1-hydroxy-1H-benzotriazole hydrate-   HPLC high pressure, high performance liquid chromatography-   conc. concentrated-   LC/MS liquid chromatography-coupled mass spectrometry-   LDA lithium diisopropylamide-   LiHMDS lithium hexamethyldisilazane-   min minute(s)-   MS mass spectrometry-   MTBE methyl tert-butyl ether-   NMR nuclear magnetic resonance spectrometry-   OAc acetate-   p para-   Ph phenyl-   PyBOP benzotriazol-1-yloxytris(pyrrolidino)phosphonium    hexafluorophosphate-   quant. quantitative (yield)-   rac racemic/racemate-   RT room temperature-   R_(t) retention time (in HPLC)-   THF tetrahydrofuran-   TMOF trimethyl orthoformate-   UV ultraviolet spectrometry-   v/v ratio by volume (of a solution)

LC/MS, GC/MS and HPLC Methods: Method 1 (LC/MS):

MS instrument type: Micromass ZQ; HPLC instrument type: Waters Alliance2795; column: Phenomenex Synergi 2.5μ MAX-RP 100A Mercury 20 mm×4 mm;mobile phase A: 1 l of water+0.5 ml of 50% strength formic acid, mobilephase B: 1 l of acetonitrile+0.5 ml of 50% strength formic acid;gradient: 0.0 min 90% A→0.1 min 90% A→3.0 min 5% A→4.0 min 5% A→4.01 min90% A; flow rate: 2 ml/min; oven: 50° C.; UV detection: 210 nm.

Method 2 (LC/MS):

Instrument: Micromass Quattro Micro MS with HPLC Agilent Series 1100;column: Thermo Hypersil GOLD 3μ 20 mm×4 mm; mobile phase A: 1 l ofwater+0.5 ml of 50% strength formic acid, mobile phase B: 1 l ofacetonitrile+0.5 ml of 50% strength formic acid; gradient: 0.0 min 100%A→3.0 min 10% A→4.0 min 10% A→4.01 min 100% A (flow rate 2.5ml/min)→5.00 min 100% A; oven: 50° C.; flow rate: 2 ml/min; UVdetection: 210 nm.

Method 3 (LC/MS):

Instrument: Micromass QuattroPremier with Waters UPLC Acquity; column:Thermo Hypersil GOLD 1.9μ 50 mm×1 mm; mobile phase A: 1 l of water+0.5ml of 50% strength formic acid, mobile phase B: 1 l of acetonitrile+0.5ml of 50% strength formic acid; gradient: 0.0 min 90% A→0.1 min 90%A→1.5 min 10% A→2.2 min 10% A; flow rate: 0.33 ml/min; oven: 50° C.; UVdetection: 210 nm.

Method 4 (LC/MS):

Instrument: Waters Acquity SQD UPLC System; column: Waters Acquity UPLCHSS T3 1.8μ 50 mm×1 mm; mobile phase A: 1 l of water+0.25 ml of 99%strength formic acid, mobile phase B: 1 l of acetonitrile+0.25 ml of 99%strength formic acid; gradient: 0.0 min 90% A→1.2 min 5% A→2.0 min 5% A;flow rate: 0.40 ml/min; oven: 50° C.; UV detection: 210-400 nm.

Method 5 (LC/MS):

MS instrument type: Micromass ZQ; HPLC instrument type: HP 1100 Series;UV DAD; column: Phenomenex Gemini 3μ 30 mm×3.00 mm; mobile phase A: 1 lof water+0.5 ml of 50% strength formic acid, mobile phase B: 1 l ofacetonitrile+0.5 ml of 50% strength formic acid; gradient: 0.0 min 90%A→2.5 min 30% A→3.0 min 5% A→4.5 min 5% A; flow rate: 0.0 min 1 ml/min2.5 min/3.0 min/4.5 min 2 ml/min; oven: 50° C.; UV detection: 210 nm.

Method 6 (LC/MS):

MS instrument type: Waters ZQ; HPLC instrument type: Agilent 1100Series; UV DAD; column: Thermo Hypersil GOLD 3μ 20 mm×4 mm; mobile phaseA: 1 l of water+0.5 ml of 50% strength formic acid, mobile phase B: 1 lof acetonitrile+0.5 ml of 50% strength formic acid; gradient: 0.0 min100% A→3.0 min 10% A→4.0 min 10% A→4.1 min 100% A (flow rate 2.5ml/min); oven: 55° C.; flow rate: 2 ml/min; UV detection: 210 nm.

Method 7 (LC/MS):

MS instrument type: Micromass ZQ; HPLC instrument type: Waters Alliance2795; column: Phenomenex Synergi 2μ Hydro-RP Mercury 20 mm×4 mm; mobilephase A: 1 l of water+0.5 ml of 50% strength formic acid, mobile phaseB: 1 l of acetonitrile+0.5 ml of 50% strength formic acid; gradient: 0.0min 90% A→2.5 min 30% A→3.0 min 5% A→4.5 min 5% A; flow rate: 0.0 min 1ml/min 2.5 min/3.0 min/4.5 min 2 ml/min; oven: 50° C.; UV detection: 210nm.

Method 8 (LC/MS):

Instrument: Micromass Platform LCZ with HPLC Agilent Series 1100;column: Thermo Hypersil GOLD 3μ 20 mm×4 mm; mobile phase A: 1 l ofwater+0.5 ml of 50% strength formic acid, mobile phase B: 1 l ofacetonitrile+0.5 ml of 50% strength formic acid; gradient: 0.0 min 100%A 0.2 min 100% A→2.9 min 30% A→3.1 min 10% A→5.5 min 10% A; flow rate:0.8 ml/min; oven: 50° C.; UV detection: 210 nm.

Method 9 (LC/MS):

Instrument: Micromass Quattro LCZ with HPLC Agilent Series 1100; column:Phenomenex Onyx Monolithic C18, 100 mm×3 mm; mobile phase A: 1 l ofwater+0.5 ml of 50% strength formic acid, mobile phase B: 1 l ofacetonitrile+0.5 ml of 50% strength formic acid; gradient: 0.0 min 90%A→2 min 65% A→4.5 min 5% A→6 min 5% A; flow rate: 2 ml/min; oven: 40°C.; UV detection: 208-400 nm.

Method 10 (LC/MS):

MS instrument type: Waters ZQ; HPLC instrument type: Waters Alliance2795; column: Phenomenex Onyx Monolithic C18, 100 mm×3 mm; mobile phaseA: 1 l of water+0.5 ml of 50% strength formic acid, mobile phase B: 1 lof acetonitrile+0.5 ml of 50% strength formic acid; gradient: 0.0 min90% A→2 min 65% A→4.5 min 5% A→6 min 5% A; flow rate: 2 ml/min; oven:40° C.; UV detection: 210 nm.

Method 11 (Chiral Analytical HPLC):

Stationary phase: Daicel Chiralcel OD-H; column: 250 mm×4 mm; flow rate:1 ml/min; temperature: RT; UV detection: 230 nm; mobile phase:

-   -   Method 11a: isohexane/isopropanol 50:50 (v/v);    -   Method 11b: isohexane/methanol/ethanol 70:15:15 (v/v/v);    -   Method 11c: isohexane/isopropanol 75:25 (v/v).

Method 12 (Chiral Preparative HPLC):

Stationary phase: Daicel Chiralpak AD-H, 5 μm; column: 250 mm×20 mm;temperature: 40° C.; UV detection: 220 nm; mobile phase:isohexane/isopropanol 80:20 (v/v); flow rate: 15 ml/min

Method 13 (Chiral Analytical HPLC):

Stationary phase: Daicel Chiralpak AD-H, 5 μm; column: 250 mm×4.6 mm;temperature: 40° C.; UV detection: 220 nm; mobile phase:isohexane/isopropanol 80:20 (v/v); flow rate: 1.0 ml/min

Method 14 (Chiral Analytical HPLC):

Stationary phase: Daicel Chiralpak AD-H, 5 μm; column: 250 mm×4.6 mm;temperature: 30° C.; UV detection: 220 nm; mobile phase:isohexane/isopropanol/20% strength trifluoroacetic acid 75:24:1 (v/v/v);flow rate: 1.0 ml/min

Method 15 (Preparative HPLC):

Instrument: Abimed Gilson Pump 305/306, Manometric Module 806; column:Grom-Sil 120 ODS-4HE, 10 μm, 250 mm×30 mm; mobile phase A: water, mobilephase B: acetonitrile; gradient: 0.0 min 30% B→3 min 30% B→30 min 95%B→42 min 95% B→42.01 min 10% B→45 min 10% B; flow rate: 50 ml/min;column temperature: RT; UV detection: 210 nm.

Method 16 (Preparative HPLC):

column: Kromasil 100 C18, 5 μm, 250 mm×20 mm; mobile phase A: 0.2%strength trifluoroacetic acid, mobile phase B: acetonitrile; isocratic55% A, 45% B; flow rate: 25 ml/min; column temperature: 30° C.; UVdetection: 210 nm.

Method 17 (Chiral Preparative HPLC):

Stationary phase: Daicel Chiralpak AD-H, 5 μm; column: 250 mm×20 mm;temperature: 40° C.; UV detection: 220 nm; mobile phase:isohexane/ethanol 80:20 (v/v); flow rate: 15 ml/min

Method 18 (Chiral Analytical HPLC):

Stationary phase: Daicel Chiralpak AS-H, 5 μm; column: 250 mm×4.6 mm;temperature: 40° C.; UV detection: 220 nm; mobile phase:isohexane/ethanol 80:20 (v/v); flow rate: 1 ml/min

Method 19 (Preparative HPLC):

Column: Grom-Sil 120 ODS-4HE, 10 μm, 250 mm×30 mm; mobile phase A:water, mobile phase B: acetonitrile; gradient: 0.0 min 10% B→3 min 10%B→30 min 95% B→42 min 95% B→42.01 min 10% B→45 min 10% B; flow rate: 50ml/min; column temperature: RT; UV detection: 210 nm.

Method 20 (GC/MS):

Instrument: Micromass GCT, GC 6890; column: Restek RTX-35, 15 m×200μm×0.33 μm; constant helium flow: 0.88 ml/min; oven: 70° C.; inlet: 250°C.; gradient: 70° C., 30° C./min 310° C. (maintained for 3 min).

Starting Materials and Intermediates Example 1A EthylN-({2-[(4-chlorophenyl)carbonyl]hydrazinyl}carbonyl)glycinate

A suspension of 12.95 g (75.9 mmol) of 4-chlorobenzohydrazide in 50 mlof dry THF was initially charged at 50° C., and a solution of 10.0 g(77.5 mmol) of ethyl 2-isocyanatoacetate in 100 ml of dry THF was addeddropwise. Initially, a solution was obtained, and then a precipitateformed. After the addition had ended, the mixture was stirred at 50° C.for a further 2 h and then allowed to stand at RT overnight. Thecrystals were isolated by filtration, washed with a little diethyl etherand dried under high vacuum. This gave 21.43 g (89% of theory) of thetitle compound.

LC/MS [Method 1]: R_(t)=1.13 min; m/z=300 (M+H)⁺

¹H-NMR (DMSO-d₆, 400 MHz): δ=1.19 (t, 3H), 3.77 (d, 2H), 4.09 (q, 2H),6.88 (br. s, 1H), 7.57 (d, 2H), 7.91 (d, 2H), 8.21 (s, 1H), 10.29 (s,1H).

Example 2A[3-(4-Chlorophenyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]acetic acid

91 ml of 3 N aqueous sodium hydroxide solution were added to 21.43 g(67.9 mmol) of the compound from Example 1A, and the mixture was heatedunder reflux overnight. After cooling to RT, the mixture was adjusted topH 1 by slow addition of about 20% strength hydrochloric acid. Theprecipitated solid was isolated by filtration, washed with water anddried at 60° C. under reduced pressure. This gave 17.55 g of the titlecompound in a purity of about 88% (90% of theory).

LC/MS [Method 1]: R_(t)=0.94 min; m/z=254 (M+H)⁺

¹H-NMR (DMSO-d₆, 400 MHz): δ=4.45 (s, 2H), 7.65-7.56 (m, 4H), 12.09 (s,1H), 13.25 (br. s, 1H).

Example 3A5-(4-Chlorophenyl)-4-(3,3,3-trifluoro-2-oxopropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one(ketone form) or5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2,2-dihydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one(hydrate form)

Under argon, 5.0 g (16.36 mmol) of the compound from Example 2A weredissolved in 200 ml of pyridine, and 17.18 g (81.8 mmol) oftrifluoroacetic anhydride were added. During the addition, thetemperature increased to about 35° C. After 30 min, the pyridine wasremoved on a rotary evaporator, and 1.5 liters of 0.5 N hydrochloricacid were added to the residue. This mixture was warmed to 70° C. andthen filtered whilst still warm. The solid was washed with a littlewater. The entire filtrate was extracted three times with ethyl acetate.The combined organic phases were washed successively with water,saturated sodium bicarbonate solution and saturated sodium chloridesolution, dried over sodium sulfate and freed from the solvent on arotary evaporator. The residue was dried under high vacuum. This gave3.56 g (68% of theory) of the title compound in the hydrate form.

LC/MS [Method 1]: R_(t)=1.51 min; m/z=306 (M+H)⁺ and 324 (M+H)⁺ (ketoneor hydrate form)

¹H-NMR (DMSO-d₆, 400 MHz): δ=3.98 (s, 2H), 7.61 (d, 2H), 7.68 (br. s,2H), 7.72 (d, 2H), 12.44 (s, 1H).

Example 4A5-(4-Chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

3.56 g (11.0 mmol) of the compound from Example 3A were dissolved in 100ml of methanol, and 3.75 g (99.5 mmol) of sodium borohydride were addedwith ice cooling. After 1.5 h, 200 ml of 1 M hydrochloric acid wereadded slowly. The methanol was removed on a rotary evaporator and theresidue was diluted with 500 ml of water and extracted three times withethyl acetate. The combined organic phases were washed with saturatedsodium bicarbonate solution and then with saturated sodium chloridesolution, dried over sodium sulfate and freed from the solvent on arotary evaporator. The residue was dried under high vacuum. This gave3.04 g (90% of theory) of the title compound.

LC/MS [Method 2]: R_(t)=1.80 min; m/z=308 (M+H)⁺

¹H-NMR (DMSO-d₆, 400 MHz): δ=3.77 (dd, 1H), 3.92 (dd, 1H), 4.34-4.23 (m,1H), 6.85 (d, 1H), 7.62 (d, 2H), 7.75 (d, 2H), 12.11 (s, 1H).

Example 5A5-(4-Chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

1.08 g (3.3 mmol) of the compound from Example 3A were dissolved in 11ml of N,N-dimethylacetamide. Atmospheric oxygen was removed byapplication of reduced pressure, and the solution was saturated withargon. Under argon, 21 mg (0.033 mmol) of(N-[(1S,2S)-(+)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amido)(p-cymene)ruthenium(II)chloride [CAS Reg.-Nr. 192139-90-5] were added to this solution. Amixture of 0.63 ml (16.6 mmol) of formic acid and 0.27 ml (1.91 mmol) oftriethylamine was then added, and the reaction was stirred withexclusion of air at RT for 48 h. For work-up, the mixture was added to10 ml of 0.1 N hydrochloric acid and extracted twice with in each case20 ml of ethyl acetate. The combined organic phases were washed withsaturated sodium bicarbonate solution, dried over sodium sulfate,filtered and concentrated under reduced pressure. The crude product waspurified by chromatography on silica gel (mobile phase:cyclohexane/ethyl acetate 3:1, then 1:1). This gave 830 mg (81% oftheory) of the target compound.

The enantiomeric excess (ee) was determined chromatographicallyaccording to Method 14 as 96%: S enantiomer R_(t)=5.73 min, R enantiomerR_(t)=6.82 min

Example 6A Methyl{3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetate(racemate)

3.04 g (9.9 mmol) of the compound from Example 4A were dissolved in 100ml of acetonitrile, and 1.07 g (9.9 mmol) of methyl chloroacetate, 2.73g (19.8 mmol) of potassium carbonate and a small spatula tip ofpotassium iodide were added. The reaction mixture was heated underreflux for 1 h and then allowed to cool to RT and filtered. The filtratewas freed from the volatile components on a rotary evaporator and theresidue was dried under high vacuum. This gave 3.70 g of the titlecompound in a purity of about 90%, (89% of theory).

LC/MS [Method 3]: R_(t)=1.10 min; m/z=380 (M+H)⁺

¹H-NMR (DMSO-d₆, 400 MHz): δ=3.70 (s, 3H), 3.84 (dd, 1H), 3.99 (dd, 1H),4.16-4.35 (m, 1H), 4.72 (s, 2H), 6.91 (d, 1H), 7.64 (d, 2H), 7.78 (d,2H).

The racemic compound from Example 6A was separated into the enantiomersby preparative HPLC on a chiral phase [sample preparation: 3.6 g ofracemate dissolved in 54 ml of ethyl acetate/isohexane (1:1 v/v),separated on the column in three portions; column: chiral silica gelphase based on the selectorpoly(N-methacryloyl-L-isoleucine-3-pentylamide), 430 mm×40 mm; mobilephase: stepped gradient isohexane/ethyl acetate 1:1→ethylacetate→isohexane/ethyl acetate 1:1; flow rate: 50 ml/min; temperature:24° C.; UV detection: 260 nm]. This gave 1.6 g of enantiomer 1 (Example7A), which eluted first, and 1.6 g of enantiomer 2 (Example 8A), whicheluted later:

Example 7A Methyl{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetate(enantiomer 1)

Enantiomer which elutes first in the racemate separation of Example 6A.

R_(t)=3.21 min [column: chiral silica gel phase based on the selectorpoly(N-methacryloyl-L-isoleucine-3-pentylamide), 250 mm×4.6 mm; mobilephase: isohexane/ethyl acetate 1:1; flow rate: 1 ml/min; UV detection:260 nm].

Example 8A Methyl{3-(4-chlorophenyl)-5-oxo-4-[(2R)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetate(enantiomer 2)

Enantiomer which elutes last in the racemate separation of Example 6A.

R_(t)=4.48 min [column: chiral silica gel phase based on the selectorpoly(N-methacryloyl-L-isoleucine-3-pentylamide), 250 mm×4.6 mm; mobilephase: isohexane/ethyl acetate 1:1; flow rate: 1 ml/min; UV detection:260 nm].

Example 9A Methyl{3-(4-chlorophenyl)-5-oxo-4-[(1E)-3,3,3-trifluoroprop-1-en-1-yl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetate

At RT, 5.0 g (13.12 mmol) of the compound from Example 8A together with1.93 g (15.8 mmol) of 4-N,N-dimethylaminopyridine were initially chargedin 70 ml of pyridine, 5.54 ml (32.92 mmol) of trifluoromethanesulfonicanhydride were added a little at a time and the mixture was stirred for18 h. For work-up, 5 ml of 1 N hydrochloric acid were added and thepyridine was removed on a rotary evaporator. The residue was taken up in50 ml of ethyl acetate and washed with 25 ml of water. The aqueous phasewas re-extracted twice with in each case 25 ml of ethyl acetate. Thecombined organic phases were dried over sodium sulfate, filtered andconcentrated under reduced pressure. The crude product was purified bychromatography on silica gel (mobile phase: cyclohexane/ethyl acetate10:1, then 4:1). This gave 3.50 g (73% of theory) of the title compound.

LC/MS [Method 4]: R_(t)=1.14 min; m/z=362 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=7.68 (s, 4H), 7.18 (d, 1H), 6.85 (dd, 1H),4.78 (s, 2H), 3.72 (s, 3H).

Example 10AMethyl[3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoropropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-acetate

1.3 g (3.59 mmol) of the compound from Example 9A and 150 mg of platinumon carbon (5%) were dissolved in 150 ml of methanol and hydrogenated atatmospheric pressure for 18 h. For work-up, the catalyst was filteredoff through kieselguhr and the filtrate was concentrated on a rotaryevaporator. Drying of the residue under high vacuum gave 1.26 g (89% oftheory) of the title compound of a purity of 92%.

LC/MS [Method 4]: R_(t)=1.00 min; m/z=364 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=2.55-2.68 (m, 2H), 3.69 (s, 3H), 4.01 (t,2H), 4.70 (s, 2H), 7.61-7.72 (m, 4H).

Example 11A2-[(4-Chlorophenyl)carbonyl]-N-(prop-2-en-1-yl)hydrazinecarboxamide

At 50° C., 5.00 g (29.3 mmol) of 4-chlorobenzohydrazide were suspendedin 150 ml of dry THF. 2.63 ml (29.9 mmol) of allyl isocyanate, dissolvedin 110 ml of dry THF, were then added dropwise. Initially, all of thestarting material dissolved, and then a fine precipitate formed. Themixture was stirred at 50° C. for 2 h. After cooling to roomtemperature, diethyl ether was added. The colorless solid was filteredoff with suction, washed with diethyl ether and dried under high vacuum.This gave 7.42 g (100% of theory) of the target compound.

LC/MS [Method 5]: R_(t)=1.51 min; MS [ESIpos]: m/z=254 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.60-3.70 (m, 2H), 5.01 (dd, 1H), 5.14 (dd,1H), 5.72-5.86 (m, 1H), 6.70 (s, 1H), 7.56 (d, 2H), 7.85-7.95 (m, 3H),10.21 (s, 1H).

Example 12A5-(4-Chlorophenyl)-4-(prop-2-en-1-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one

26.8 g (106 mmol) of2-[(4-chlorophenyl)carbonyl]-N-(prop-2-en-1-yl)hydrazinecarboxamide fromExample 11A were suspended in 210 ml of 3 M aqueous sodium hydroxidesolution, and the mixture was heated under reflux for 20 h. Aftercooling, the pH was adjusted to 10 using semiconcentrated hydrochloricacid. The precipitated colorless solid was filtered off with suction,washed with water until neutral and then stirred with methanol. Byfiltration, the mixture was freed from insoluble components, thefiltrate was concentrated under reduced pressure on a rotary evaporatorand the residue was dried under high vacuum. This gave 21.5 g (86.4% oftheory) of the title compound as a colorless solid.

LC/MS [Method 5]: R_(t)=1.79 min; MS [ESIpos]: m/z=236 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=4.30-4.35 (m, 2H), 4.91 (dd, 1H), 5.11 (dd,1H), 5.76-5.90 (m, 1H), 7.58 (d, 2H), 7.65 (d, 2H), 12.05 (s, 1H).

Example 13A5-(4-Chlorophenyl)-2-(prop-2-yn-1-yl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

300 mg (0.98 mmol) of the compound from Example 4A were dissolved in 10ml of acetonitrile, and 122 mg (1.02 mmol) of 3-bromo-1-propyne and 270mg (1.95 mmol) of potassium carbonate were added. The mixture was heatedat reflux for 1 h. For work-up, the reaction mixture was allowed to coolto RT and about 10 ml of water were added. The mixture was extractedtwice with in each case 15 ml of ethyl acetate. The combined organicphases were dried over sodium sulfate, filtered and concentrated underreduced pressure. The crude product was purified chromatographically[Method 19]. This gave 166 mg (49% of theory) of the target compound.

LC/MS [Method 4]: R_(t)=0.97 min; m/z=346 (M+H)⁺

¹H-NMR (CDCl₃, 400 MHz): δ=2.38 (t, 1H), 3.94-4.09 (m, 1H), 4.43-4.54(m, 1H), 4.68 (d, 2H), 4.73-4.78 (m, 1H), 7.50 (d, 2H), 7.57 (d, 2H).

Example 14A5-(4-Chlorophenyl)-2-(prop-2-yn-1-yl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

1110 mg (3.61 mmol) of the compound from Example 5A were dissolved in 30ml of acetonitrile, and 451 mg (3.79 mmol) of 3-bromo-1-propyne and 2.35g (7.22 mmol) of cesium carbonate were added. The mixture was heatedunder reflux for 1 h. For work-up, the reaction mixture was allowed tocool to RT, and about 30 ml of water were added. The mixture wasextracted twice with in each case 30 ml of ethyl acetate. The combinedorganic phases were dried over sodium sulfate, filtered and concentratedunder reduced pressure. The crude product was purified by chromatographyon silica gel (mobile phase: cyclohexane/ethyl acetate 10:1, then 3:1).This gave 203 mg (16% of theory) of the title compound.

LC/MS [Method 3]: R_(t)=1.11 min; m/z=346 (M+H)⁺

¹H-NMR (CDCl₃, 400 MHz): δ=2.38 (t, 1H), 3.94-4.09 (m, 1H), 4.43-4.54(m, 1H), 4.68 (d, 2H), 4.73-4.78 (m, 1H), 7.50 (d, 2H), 7.57 (d, 2H).

Example 15A Methyl3-{[3-(4-chlorophenyl)-1-(2-methoxy-2-oxoethyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]methyl}benzenecarboxylate

200 mg (0.75 mmol) ofmethyl[3-(4-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetate[preparation according to WO 2007/134862 Example 222A] were suspended in7.5 ml of acetone, 365 mg (1.12 mmol) of cesium carbonate and 223 mg(0.97 mmol) of methyl 3-bromomethylbenzoate were added and the mixturewas heated at the boil for 1 h. After cooling, the mixture was filteredthrough Extrelut and the filter cake was rinsed with acetone. Thefiltrate was concentrated under reduced pressure and the residue waspurified by chromatography on silica gel (mobile phase:cyclohexane/ethyl acetate 4:1→1:1). The target compound was obtained asa colorless foam (165 mg, 53% of theory).

MS [DCI]: m/z=433 (M+NH₄)⁺, 416 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.71 (s, 3H), 3.82 (s, 3H), 4.75 (s, 2H),5.08 (s, 2H), 7.32 (d, 1H), 7.46 (t, 1H), 7.55 (s, 4H), 7.66 (s, 1H),7.82 (d, 1H).

Example 16A Methyl3-{[3-(4-chlorophenyl)-1-(2-hydrazino-2-oxoethyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]methyl}benzenecarboxylate

172 mg (0.41 mmol) of the compound from Example 15A were suspended in 1ml of ethanol, and 40 μl (0.83 mmol) of hydrazine hydrate were added.The mixture was heated under reflux for 4 h and then allowed to stand atroom temperature for 18 h. The reaction was concentrated under reducedpressure on a rotary evaporator and the residue was dried under highvacuum. This gave 161 mg (94% of theory) of the target compound as acolorless solid.

MS [DCI]: m/z=433 (M+NH₄)⁺, 416 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.82 (s, 3H), 4.31 (d, 2H), 4.43 (s, 2H),5.05 (s, 2H), 7.37 (d, 1H), 7.42-7.57 (m, 5H), 7.71 (s, 1H), 7.83 (d,1H), 9.30 (t, 1H).

The following compounds were obtained in an analogous manner:

Start- ing Exam- mate- Analytical ple Name Structure rial data 17A2-[3-(4-chloro- phenyl)-4-(4- methoxy- benzyl)-5-oxo- 4,5-dihydro-1H-1,2,4- triazol-1-yl]- acetohydrazide

WO 2007/ 134862 Ex. 78A LC/MS [Method 5]: R_(t) = 1.88 min; MS [ESIpos]:m/z = 388 (M + H)⁺ 18A 2-[3-(4-chloro- phenyl)-5-oxo- 4-(3,3,3-tri-fluoro-2- hydroxy- propyl)-4,5- dihydro-1H- 1,2,4-triazol- l-yl]aceto-hydrazide

Ex. 6A LC/MS [Method 5]: R_(t) = 1.83 min; MS [ESIpos]: m/z = 380 (M +Na)⁺ 19A 2-{3-(4-chloro- phenyl)-5-oxo- 4-[(2S)-3,3,3- trifluoro-2-hydroxy- propyl]-4,5- dihydro-1H- 1,2,4-triazol- 1-yl}aceto- hydrazide(enantiomer I)

Ex. 7A ¹H-NMR (400 MHz, DMSO- d₆): δ = 3.33 (br. s, 2H), 3.77-3.86 (m,1H), 3.91-3.99 (m, 1H), 4.33- 4.43 (m, 2H), 6.93 (br. s, 1H), 7.61-7.66(m, 2H), 7.72-7.79 (m, 2H), 9.21- 9.30 (br. s, 1H). 20A 2-{3-(4-chloro-phenyl)-5-oxo- 4-[(2R)-3,3,3- trifluoro-2- hydroxy- propyl]-4,5-dihydro-1H- 1,2,4-triazol- 1-yl}aceto- hydrazide (enantiomer II)

Ex. 8A LC/MS [Method 3]: R_(t) = 0.90 min; MS [ESIpos]: m/z = 380 (M +H)⁺

Example 21A2-[3-(4-Chlorophenyl)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetohydrazide

50 mg (0.17 mmol) of[3-(4-chlorophenyl)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-aceticacid [preparation according to WO 2007/134862 Example 88A] weredissolved in 0.4 ml of methanol and diluted with 0.6 ml of toluene, and128 μl (0.26 mmol) of trimethylsilyldiazomethane solution (2 M inhexanes) were then added dropwise until a slight yellow color remained.The reaction was stirred for 1 h and then evaporated to dryness. Theresidue was taken up in 1 ml of ethanol, 43 mg (0.85 mmol) of hydrazinehydrate were added and the mixture was stirred under reflux for 2.5 h.After cooling, the solution was concentrated under reduced pressure andthe residue was dried under high vacuum. This gave 54 mg (96% of theory)of the title compound in a purity of 93% as a colorless solid.

LC/MS [Method 5]: R_(t)=1.65 min; MS [ESIpos]: m/z=308 (M+H)⁺.

The two compounds below were obtained in an analogous manner:

Start- ing Exam- mate- Analytical ple Name Structure rial data 22A2-[3-(5-chloro- thiophen-2-yl)- 4-(2-fluoro- benzyl)-5-oxo- 4,5-dihydro-1H-1,2,4- triazol-1-yl]- acetohydrazide

WO 2007/ 134862 Ex. 154A LC/MS [Method 7]: R_(t) = 1.73 min; MS[ESIpos]: m/z = 382 (M + H)⁺ 23A 2-[3-(4-chloro- phenyl)-5-oxo-4-(3,3,3-tri- fluoropropyl)- 4,5-dihydro- 1H-1,2,4- triazol-1-yl]-acetohydrazide

10A LC/MS [Method 6]: R_(t) = 1.75 min; MS [ESIpos]: m/z = 384 (M + H)⁺

Example 24A[3-(5-Chlorothiophen-2-yl)-4-(2-fluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetonitrile

A mixture of 250 mg (0.81 mmol) of5-(5-chloro-2-thienyl)-4-(2-fluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one[preparation according to WO 2007/134862 Example 154A], 67 μl (0.97mmol) of bromoacetonitrile and 223 mg (1.61 mmol) of potassium carbonatewas stirred in 8 ml of dry DMF at an oil bath temperature of 100° C. for1 h. After cooling, the mixture was filtered through kieselguhr, thefiltrate was concentrated under reduced pressure and the residue waspartitioned between MTBE and water. The organic phase was washedsuccessively with 10 ml of water and 10 ml of saturated sodium chloridesolution, dried over sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified chromatographically on silicagel (mobile phase: cyclohexane/ethyl acetate 4:1). This gave 258 mg (92%of theory) of the target compound as a slightly yellowish solid.

MS [DCI]: m/z=366 (M+NH₄)⁺, 349 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=4.81 (s, 2H), 5.11 (s, 2H), 6.87 (d, 1H),6.97 (s, 1H), 7.05-7.16 (m, 3H), 7.28-7.36 (m, 1H).

Example 25A(1Z)-2-[3-(5-Chlorothiophen-2-yl)-4-(2-fluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N′-hydroxyethaneimidamide

250 mg (0.66 mmol) of the compound from Example 24A and 92 mg (1.32mmol) of hydroxylamine hydrochloride were suspended in 3.3 ml ofethanol, and the mixture was heated to the boil. 193 μl (1.39 mmol) oftriethylamine were added to the hot solution and heating under refluxwas continued for a further 1 h. On cooling of the reaction, a colorlesssolid crystallized out; this solid was filtered off and washed with alittle ethanol. This gave 174 mg (69% of theory) of the target compoundas a colorless solid. The mother liquor was concentrated under reducedpressure on a rotary evaporator, and the residue was partitioned betweenwater and ethyl acetate. The organic phase was washed successively with10 ml of water and 10 ml of saturated sodium chloride solution, driedover sodium sulfate, filtered and concentrated under reduced pressure.This gave a further 69 mg (24% of theory) of the target compound in apurity of 87% as a slightly yellowish solid.

MS [ESIpos]: m/z=382 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=4.36 (s, 2H), 5.11 (s, 2H), 5.46 (s, 2H),7.04-7.12 (m, 1H), 7.12-7.28 (m, 4H), 7.30-7.41 (m, 1H), 9.27 (s, 1H).

Example 26A 1-Amino-3-[3-(trifluoromethyl)phenyl]acetone hydrochloride

Under argon and with ice cooling, 1.13 g (11.8 mmol) of diformylamidesodium salt were added a little at a time to a solution of 2.67 g (11.2mmol) of 1-chloro-3-[3-(trifluoromethyl)phenyl]propan-2-one in 11 ml ofDMF. The mixture was stirred in an ice bath for 1 h and then at RTovernight. The mixture was then diluted with 25 ml of ethyl acetate andwashed successively with in each case 15 ml of 0.5 N hydrochloric acid,water, saturated sodium bicarbonate solution and once more with water.The organic phase was dried over sodium sulfate, filtered andconcentrated under reduced pressure. The dark oily residue waspre-purified on a short silica gel column (mobile phase:dichloromethane/ethanol 95:5). This gave 2.0 g of a dark-brown solid.This was taken up in 25 ml of a 7 N solution of hydrogen chloride inisopropanol, and the mixture was stirred overnight. The solvent wasremoved under reduced pressure on a rotary evaporator, and the residuewas dissolved in about 15 ml of methanol. 100 ml of diethyl ether werestirred into this solution, and the precipitated solid was isolated byfiltration. The filter cake was washed with about 10 ml of diisopropylether and dried under high vacuum. This gave 0.79 g (28% of theory) ofthe target compound as a brown solid.

LC/MS [Method 8]: R_(t)=2.30 min; MS [ESIpos]: m/z=218 (M−HCl)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=4.00-4.11 (m, 4H), 7.49-7.70 (m, 4H), 8.17(br. d, 1H).

Example 27A2-[3-(4-Chlorophenyl)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-{2-oxo-3-[3-(tri-fluoromethyl)phenyl]propyl}acetamide

391 mg (2.90 mmol) of HOBt and 513 mg (2.67 mmol) of EDC were added to asolution of 654 mg (2.23 mmol) of[3-(4-chlorophenyl)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]aceticacid [preparation according to WO 2007/134862 Example 88A] and 650 mg(2.56 mmol) of the compound from Example 26A in 4.4 ml of dry DMF. 465μl (2.67 mmol) of N,N-diisopropylethylamine were then added, and thereaction was stirred overnight. For work-up, the reaction was dilutedwith 20 ml of ethyl acetate and extracted twice with in each case 15 mlof water. The organic phase was dried over sodium sulfate, filtered andconcentrated under reduced pressure. The residue that remained wasrecrystallized from acetonitrile. This gave 610 mg (56% of theory) ofthe target compound as very fine colorless crystals. A further 84 mg (8%of theory) of the target compound were obtained from a secondcrystallization of the concentrated mother liquor in the form ofslightly yellowish crystals.

MS [ESIpos]: m/z=493 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=0.73-0.83 (m, 2H), 0.97-1.09 (m, 2H),2.94-3.04 (m, 1H), 3.80 (s, 2H), 4.25 (d, 2H), 4.53 (s, 2H), 6.91-7.02(m, 1H), 7.39 (d, 1H), 7.43-7.51 (m, 4H), 7.57 (d, 1H), 7.71 (d, 2H).

Example 28A2-[(5-Bromopyridin-3-yl)methyl]-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

300 mg (0.98 mmol) of the compound from Example 4A and 953 mg (2.93mmol) of cesium carbonate were dissolved in 4 ml of DMF, and 261 mg(1.10 mmol) of 3-bromo-5-(chloromethyl)-pyridine hydrochloride wereadded. The mixture was stirred initially at 40° C. for 20 h and then at70° C. for 24 h. To bring the reaction to completion, a further 130 mg(0.55 mmol) of 3-bromo-5-(chloromethyl)pyridine hydrochloride and 450 mg(1.38 mmol) of cesium carbonate were then added, and the reaction wasstirred at 70° C. for another 20 h. After cooling to RT, 10 ml of waterwere added and the mixture was extracted three times with in each case10 ml of ethyl acetate. The combined organic phases were dried overmagnesium sulfate, filtered and concentrated under reduced pressure. Thecrude product was purified by preparative HPLC [Method 19]. This gave263 mg (56% of theory) of the target compound.

LC/MS [Method 4]: R_(t)=1.07 min; MS [ESIpos]: m/z=477 and 479 (M+H)⁺.

Example 29A2-[(5-Bromopyridin-3-yl)methyl]-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

171 mg (0.56 mmol) of the compound from Example 5A and 543 mg (1.67mmol) of cesium carbonate were dissolved in 11 ml of acetonitrile, and135 mg (0.56 mmol) of 3-bromo-5-(chloromethyl)pyridine hydrochloridewere added. The mixture was stirred at 65° C. for 5 h. After cooling toRT, 10 ml of water were added and the mixture was extracted three timeswith in each case 10 ml of ethyl acetate. The combined organic phaseswere dried over sodium sulfate, filtered and concentrated under reducedpressure. The crude product was purified by preparative HPLC [Method19]. This gave 102 mg (38% of theory) of the target compound.

LC/MS [Method 4]: R_(t)=1.05 min; MS [ESIpos]: m/z=477 and 479 (M+H)⁺.

Example 30A5-(4-Chlorophenyl)-2-[(5-chloro-2-thienyl)methyl]-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

119 mg (0.39 mmol) of the compound from Example 5A and 107 mg (0.77mmol) of potassium carbonate were dissolved in 5 ml of acetonitrile, and65 mg (0.39 mmol) of 2-chloro-5-(chloromethyl)thiophene were added. Themixture was stirred under reflux for 2 h. After cooling to RT, 10 ml ofwater were added and the mixture was extracted three times with in eachcase 10 ml of ethyl acetate. The combined organic phases were washedwith 10 ml of saturated sodium chloride solution, dried over sodiumsulfate, filtered and concentrated under reduced pressure. The crudeproduct was purified by chromatography on silica gel (mobile phase:cyclohexane/ethyl acetate 10:1→8:1→5:1→1:1). This gave 114 mg (65% oftheory) of the target compound.

LC/MS [Method 4]: R_(t)=1.20 min; MS [ESIpos]: m/z=438 and 440 (M+H)⁺.

Example 31A5-(4-Chlorophenyl)-2-[(2-chloro-1,3-thiazol-5-yl)methyl]-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

500 mg (1.63 mmol) of the compound from Example 5A and 449 mg (3.25mmol) of potassium carbonate were dissolved in 4 ml of acetonitrile, and287 mg (1.71 mmol) of 2-chloro-5-(chloromethyl)-1,3-thiazole were added.The mixture was stirred at 80° C. for 1.5 h. After cooling to RT, 10 mlof water were added and the mixture was extracted three times with ineach case 10 ml of ethyl acetate. The combined organic phases werewashed with 10 ml of saturated sodium chloride solution, dried oversodium sulfate, filtered and concentrated under reduced pressure. Thecrude product was purified by chromatography on silica gel (mobilephase: cyclohexane/ethyl acetate 7:1, then 1:1). This gave 619 mg (87%of theory) of the target compound.

LC/MS [Method 3]: R_(t)=1.24 min; MS [ESIpos]: m/z=439 and 441 (M+H)⁺.

Example 32A Ethyl 1-(2,6-dichlorobenzyl)-1H-imidazol-5-carboxylate

258 mg (1.84 mmol) of ethyl 1H-imidazole-4-carboxylate together with 486mg (2.03 mmol) of 2,6-dichlorobenzyl bromide were dissolved in 7 ml ofDMF, and 720 mg (2.21 mmol) of cesium carbonate were added. The mixturewas stirred at 80° C. for 16 h. After cooling to RT, 10 ml of water wereadded and the mixture was extracted twice with in each case 10 ml ofethyl acetate. The combined organic phases were dried over sodiumsulfate and freed from the solvent on a rotary evaporator. The crudeproduct was purified chromatographically [Method 19]. This gave 220 mg(40% of theory) of the target compound.

LC/MS [Method 3]: R_(t)=1.03 min; MS [ESIpos]: m/z=299 and 301 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=1.37 (t, 3H), 4.34 (q, 2H), 5.44 (s, 2H),7.27-7.33 (m, 1H), 7.37-7.43 (m, 2H), 7.68 (d, 2H).

A further fraction gave 110 mg (20% of theory) of the regioisomer ethyl1-(2,6-dichlorobenzyl)-1H-imidazole-4-carboxylate:

LC/MS [Method 3]: R_(t)=1.12 min; MS [ESIpos]: m/z=299 and 301 (M+H)⁺.

Example 33A Ethyl1-(2,6-dichlorobenzyl)-4-nitro-1H-imidazole-2-carboxylate

1000 mg (5.4 mmol) of ethyl 4-nitro-1H-imidazole-2-carboxylate togetherwith 1426 mg (5.94 mmol) of 2,6-dichlorobenzyl bromide were dissolved in37 ml of DMF, and 2112 mg (6.48 mmol) of cesium carbonate were added.The mixture was stirred at 75° C. for 4 h. After cooling to RT, themixture was added to 100 ml of ice-water. The precipitated product wasfiltered off and washed with water. The beige solid was dried under highvacuum. This gave 1500 mg (81% of theory) of the target compound.

LC/MS [Method 1]: R_(t)=2.05 min; MS [ESIpos]: m/z=344 and 346 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=1.35 (t, 3H), 4.41 (q, 2H), 5.96 (s, 2H),7.53 (dd, 1H), 7.59-7.64 (m, 2H), 7.96 (s, 1H).

Example 34A Methyl 1-(2-chlorophenyl)-1H-imidazole-4-carboxylate

200 mg (1.59 mmol) of methyl 1H-imidazole-4-carboxylate, 496 mg (3.17mmol) of 2-chlorophenylboronic acid, 100 mg of 3 Å molecular sieve and432 mg (2.28 mmol) of copper(II) acetate were initially charged in 2 mlof dichloromethane, and 256 μl (3.17 mmol) of pyridine were added. Themixture was stirred at RT for 20 h. For work-up, the mixture wasfiltered through a little kieselguhr, the filter residue was rinsed withabout 15 ml of ethyl acetate and the combined filtrates were washed with5 ml of water. The organic phase was dried over sodium sulfate, filteredand concentrated under reduced pressure. The crude product was purifiedby chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate3:1→1:1→1:3). This gave 55 mg (13% of theory) of the target compound.

LC/MS [Method 3]: R_(t)=0.90 min; MS [ESIpos]: m/z=237 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.79 (s, 3H), 7.53-7.58 (m, 2H), 7.64 (dd,1H), 7.70-7.77 (m, 1H), 8.05 (d, 1H), 8.20 (d, 1H).

Example 35A Ethyl 1-(2-chlorophenyl)-1H-pyrazole-4-carboxylate

400 mg (2.85 mmol) of ethyl 1H-pyrazole-4-carboxylate, 893 mg (5.71mmol) of 2-chlorophenylboronic acid, 100 mg of 3 Å molecular sieve and778 mg (4.28 mmol) of copper(II) acetate were initially charged in 2 mlof dichloromethane, and 461 μl (5.71 mmol) of pyridine were added. Themixture was stirred at RT for 20 h. For work-up, the mixture wasfiltered through a little kieselguhr, the filter residue was rinsed withabout 10 ml of dichloromethane and the combined filtrates wereconcentrated under reduced pressure. The crude product was purified bychromatography on silica gel (mobile phase: cyclohexane/ethyl acetate10:1, then 5:1). This gave 71 mg (10% of theory) of the target compound.

LC/MS [Method 3]: R_(t)=1.15 min; MS [ESIpos]: m/z=251 (M+H)⁺.

Example 36A [1-(2,6-Dichlorobenzyl)-1H-imidazol-5-yl]methanol

220 mg (0.74 mmol) of the compound from Example 32A were dissolved in 3ml of THF, and 0.74 ml (0.74 mmol) of a 1 M solution of lithium aluminumhydride in THF was added dropwise at 0° C. The mixture was stirred at RTfor 1 h. For work-up, 5 ml of a saturated potassium sodium tartratesolution were added with ice cooling, the mixture was diluted with 10 mlof ethyl acetate and the precipitated solid was filtered off. The crudeproduct was purified chromatographically [Method 19]. This gave 188 mg(99% of theory) of the target compound.

LC/MS [Method 3]: R_(t)=0.51 min; MS [ESIpos]: m/z=257 and 259 (M+H)⁺.

Example 37A [1-(2,6-Dichlorobenzyl)-4-nitro-1H-imidazol-2-yl]methanol

1200 mg (3.5 mmol) of the compound from Example 33A together with 15 mg(0.35 mmol) of lithium chloride were dissolved in 53 ml1,2-dimethoxyethane, and 198 mg (5.23 mmol) of sodium borohydride wereadded at 0° C. The mixture was stirred at RT for 1 h. For work-up, 25 mlof a saturated potassium sodium tartrate solution were added with icecooling and the mixture was extracted with 50 ml of ethyl acetate. Theorganic phase was dried over sodium sulfate, filtered and concentratedunder reduced pressure. The crude product was purified by chromatographyon silica gel (mobile phase: ethyl acetate/cyclohexane 1:1). This gave800 mg (76% of theory) of the target compound.

LC/MS [Method 5]: R_(t)=1.82 min; MS [ESIpos]: m/z=302 and 304 (M+H)⁺.

Example 38A [1-(2-Chlorophenyl)-1H-imidazol-4-yl]methanol

50 mg (0.21 mmol) of the compound from Example 34A were dissolved in 1ml of THF, and 222 μl (0.22 mmol) of a 1 N solution of lithium aluminumhydride in THF were added at −10° C. Over a period of one hour, themixture was then warmed to RT. For work-up, 2 ml of water and 5 ml ofsaturated potassium sodium tartrate solution were added and the mixturewas extracted twice with in each case 10 ml of ethyl acetate. Thecombined organic phases were dried over sodium sulfate, filtered andconcentrated under reduced pressure. This gave 34 mg (56% of theory) ofthe target compound in a purity of 73%.

LC/MS [Method 3]: R_(t)=0.34 min; MS [ESIpos]: m/z=209 (M+H)⁺.

Example 39A [1-(2-Chlorophenyl)-1H-pyrazol-4-yl]methanol

80 mg (0.32 mmol) of the compound from Example 35A were dissolved in 2ml of THF, and 335 μl (0.34 mmol) of a 1 N solution of lithium aluminumhydride in THF were added at −10° C. Over a period of one hour, themixture was then warmed to RT. For work-up, 2 ml of water and 5 ml ofsaturated potassium sodium tartrate solution were added and the mixturewas extracted twice with in each case 10 ml of ethyl acetate. Thecombined organic phases were dried over sodium sulfate, filtered andconcentrated under reduced pressure. This gave 61 mg (83% of theory) ofthe target compound in a purity of 91%.

LC/MS [Method 3]: R_(t)=0.76 min; MS [ESIpos]: m/z=209 (M+H)⁺.

Example 40A 5-(Chloromethyl)-1-(2,6-dichlorobenzyl)-1H-imidazole

45 mg (0.18 mmol) of the compound from Example 36A together with 27 mg(0.26 mmol) of triethylamine were dissolved in 1 ml of toluene, and 25mg (0.21 mmol) of thionyl chloride were added dropwise at RT. Themixture was stirred at RT for 1 h. Under reduced pressure, the reactionmixture was freed from all volatile components. This gave 48 mg (99% oftheory) of the target compound, which was reacted further without anyfurther purification.

Example 41A 2-(Chloromethyl)-1-(2,6-dichlorobenzyl)-4-nitro-1H-imidazole

210 mg (0.70 mmol) of the compound from Example 37A were dissolved in 10ml of dichloromethane, and 145 μl (1.04 mmol) of triethylamine and 61 μl(0.83 mmol) of thionyl chloride were added at 0° C. The mixture wasstirred at RT for 24 h. A further 200 μl (2.72 mmol) of thionyl chloridewere then added, and the mixture was stirred under reflux for 15 min.Under reduced pressure, the reaction mixture was then freed from allvolatile components. This gave, in a purity of 88%, 200 mg (80% oftheory) of the target compound, which was reacted further without anyfurther purification.

LC/MS [Method 3]: R_(t)=1.16 min; MS [ESIpos]: m/z=320 and 322 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=5.03 (s, 2H), 5.61 (s, 2H), 7.52-7.57 (m,1H), 7.62-7.65 (m, 2H), 7.86-7.88 (m, 1H).

Example 42A 4-(Bromomethyl)-1-(2-chlorophenyl)-1H-imidazole

48 mg (0.16 mmol) of the compound from Example 38A and 63 mg (0.24 mmol)of triphenylphosphine were dissolved in 1.6 ml of THF, and 80 mg (0.24mmol) of carbon tetrabromide were added at RT. The mixture was thenstirred at RT for 16 h. For work-up, the mixture was filtered through 20g of kieselguhr, the filter residue was rinsed with ethyl acetate andthe filtrate was concentrated under reduced pressure. The residue waspurified chromatographically on silica gel (mobile phase:cyclohexane/ethyl acetate 5:1, then 1:1). This gave 17 mg (39% oftheory) of the target compound which was immediately reacted further.

LC/MS [Method 4]: R_(t)=0.34 min; MS [ESIpos]: m/z=209 (M-Br+OH+H)⁺.

Example 43A 4-(Bromomethyl)-1-(2-chlorophenyl)-1H-pyrazole

61 mg (0.27 mmol) of the compound from Example 39A and 105 mg (0.40mmol) of triphenylphosphine were dissolved in 1.6 ml of THF, and 132 mg(0.40 mmol) of carbon tetrabromide were added at RT. The mixture wasthen stirred at RT for 16 h. For work-up, the mixture was filteredthrough 20 g of kieselguhr, the filter residue was rinsed with ethylacetate and the filtrate was concentrated under reduced pressure. Theresidue was purified chromatographically on silica gel (mobile phase:cyclohexane/ethyl acetate 10:1, then 5:1). This gave 30 mg (42% oftheory) of the target compound which was immediately reacted further.

LC/MS [Method 4]: R_(t)=0.67 min; MS [ESIpos]: m/z=209 (M-Br+OH+H)⁺.

Example 44A Ethyl 2-(2-chlorophenyl)-1,3-oxazole-5-carboxylate

Under argon, 300 mg (1.71 mmol) of ethyl2-bromo-1,3-oxazole-5-carboxylate together with 422 mg (2.56 mmol) of2-chlorophenylboronic acid were dissolved in 7 ml of toluene, and 67 mg(0.17 mmol) of 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl,78 mg (0.085 mmol) of tris(dibenzylideneacetone)dipalladium and 725 mg(3.42 mmol) of potassium phosphate were added successively. The mixturewas heated to 110° C. and stirred at this temperature for 20 h. Forwork-up, the reaction mixture was allowed to cool to RT and diluted with20 ml of ethyl acetate and 20 ml of water. After phase separation, theaqueous phase was extracted two more times with in each case 20 ml ofethyl acetate. The combined organic phases were dried over magnesiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by preparative HPLC [Method 19]. This gave 217 mg (50% oftheory) of the target compound.

LC/MS [Method 3]: R_(t)=1.21 min; MS [ESIpos]: m/z=252 (M+H)⁺.

Example 45A Ethyl 2-(2,3-dichlorophenyl)-1,3-oxazole-5-carboxylate

300 mg (1.71 mmol) of ethyl 2-bromo-1,3-oxazole-5-carboxylate werereacted analogously to the process of Example 44A. This gave 174 mg (31%of theory) of the target compound in a purity of 87%.

LC/MS [Method 4]: R_(t)=1.19 min; MS [ESIpos]: m/z=286 and 288 (M+H)⁺.

Example 46A Methyl 5-(2-chlorophenyl)thiophene-2-carboxylate

Under argon, 310 mg (1.40 mmol) of methyl 5-bromothiophene-2-carboxylatetogether with 328 mg (2.10 mmol) of 2-chlorophenylboronic acid weredissolved in 10 ml of dioxane, and 81 mg (0.07 mmol) oftetrakis(triphenylphosphine)palladium(0) were added. The mixture washeated to 110° C., 1.4 ml (2.80 mmol) of 2 M aqueous sodium carbonatesolution were added and the mixture was stirred at this temperature for20 h. For work-up, the reaction mixture was allowed to cool to RT anddiluted with 20 ml of ethyl acetate and 20 ml of water. After phaseseparation, the aqueous phase was extracted two more times with in eachcase 20 ml of ethyl acetate. The combined organic phases were dried oversodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified chromatographically on silica gel (mobile phase:cyclohexane/ethyl acetate 15:1, then 10:1). This gave 289 mg (61% oftheory) of the target compound in a purity of 75%.

LC/MS [Method 2]: R_(t)=2.58 min; MS [ESIpos]: m/z=253 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.85 (s, 3H), 7.45-7.48 (m, 2H), 7.53 (d,1H), 7.64 (dd, 1H), 7.73 (dd, 1H), 7.85 (d, 1H).

Example 47A Methyl 5-(2,3-dichlorophenyl)thiophene-2-carboxylate

300 mg (1.36 mmol) of methyl 5-bromothiophene-2-carboxylate were reactedanalogously to the process of Example 46A. This gave 273 mg (58% oftheory) of the target compound in a purity of 83%.

LC/MS [Method 4]: R_(t)=1.30 min; MS [ESIpos]: m/z=287 (M+H)⁺.

Example 48A 5-(2-Chlorophenyl)thiophene-2-carboxylic acid

289 mg (1.14 mmol) of the compound from Example 46A were dissolved in 2ml of THF/methanol (1:1), and 1.14 ml (2.29 mmol) of 2 M aqueous sodiumhydroxide solution were added. The reaction mixture was stirred at 80°C. for 2 h. After cooling to RT, the solvent was removed on a rotaryevaporator and the residue was taken up in 5 ml of water and washed with5 ml of ethyl acetate. The aqueous phase was acidified with 1 Nhydrochloric acid and extracted twice with in each case 5 ml of ethylacetate. The combined organic phases were dried over sodium sulfate,filtered and concentrated under reduced pressure. This gave, in a purityof 91%, 218 mg (73% of theory) of the target compound.

LC/MS [Method 2]: R_(t)=2.16 min; MS [ESIpos]: m/z=239 (M+H)⁺.

Example 49A 5-(2,3-Dichlorophenyl)thiophene-2-carboxylic acid

273 mg (0.79 mmol) of the compound from Example 47A were reactedanalogously to the process of Example 48A. This gave, in a purity of92%, 228 mg (97% of theory) of the target compound.

LC/MS [Method 4]: R_(t)=1.07 min; MS [ESIpos]: m/z=271 and 273 (M−H)⁻.

Example 50A [2-(2-Chlorophenyl)-1,3-oxazol-5-yl]methanol

217 mg (0.86 mmol) of the compound from Example 44A were reactedanalogously to the process of Example 39A. This gave, in a purity of89%, 181 mg (89% of theory) of the target compound.

LC/MS [Method 4]: R_(t)=0.75 min; MS [ESIpos]: m/z=210 (M+H)⁺.

Example 51A [2-(2,3-Dichlorophenyl)-1,3-oxazol-5-yl]methanol

186 mg (0.65 mmol) of the compound from Example 45A were reactedanalogously to the process of Example 39A. This gave, in a purity of86%, 89 mg (48% of theory) of the target compound.

LC/MS [Method 4]: R_(t)=0.87 min; MS [ESIpos]: m/z=244 and 246 (M+H)⁺.

Example 52A [5-(2-Chlorophenyl)-2-thienyl]methanol

350 mg (1.47 mmol) of the compound from Example 48A were dissolved in 5ml of THF, the mixture was cooled to 0° C. and 0.20 ml (1.47 mmol) oftriethylamine and 0.21 ml (1.61 mmol) of isobutyl chloroformate wereadded. The mixture was stirred at 0° C. for 1 h. The suspension was thenfiltered through a Seitz frit into a flask cooled to 0° C., and theresidue was rinsed with about 2 ml of THF. With vigorous stirring, thefiltrate obtained was then added to a solution, cooled to 0° C., of 166mg (4.40 mmol) of sodium borohydride in 2 ml of water. After 1 h, 5 mlof saturated sodium bicarbonate solution were added and the mixture waswarmed to RT. The mixture was extracted with 15 ml of ethyl acetate. Theorganic phase was washed successively with in each case 5 ml ofsaturated sodium bicarbonate solution and saturated sodium chloridesolution. After drying over sodium sulfate, the mixture was filtered andconcentrated under reduced pressure. The crude product was purified bychromatography on silica gel (mobile phase: cyclohexane/ethyl acetate10:1, then 5:1). This gave 252 mg (63% of theory) of the title compoundin a purity of 83%.

LC/MS [Method 3]: R_(t)=1.12 min; MS [ESIpos]: m/z=206 (M−H₂O+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=4.66 (d, 2H), 5.54 (t, 1H), 6.99 (d, 1H),7.27 (d, 1H), 7.33-7.43 (m, 2H), 7.55-7.62 (m, 2H).

Example 53A [5-(2,3-Dichlorophenyl)-2-thienyl]methanol

268 mg (0.98 mmol) of the compound from Example 49A were reactedanalogously to the process of Example 52A. This gave, in a purity of87%, 184 mg (63% of theory) of the target compound.

LC/MS [Method 4]: R_(t)=1.10 min; MS [ESIpos]: m/z=241 and 243(M−H₂O+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=4.67 (d, 2H), 5.58 (t, 1H), 7.01 (d, 1H),7.29 (d, 1H), 7.39-7.44 (m, 1H), 7.55-7.58 (m, 1H), 7.62-7.66 (m, 1H).

Example 54A 5-(Bromomethyl)-2-(2-chlorophenyl)-1,3-oxazole

181 mg (0.77 mmol) of the compound from Example 50A and 242 mg (0.92mmol) of triphenylphosphine were dissolved in 4 ml of THF, and 306 mg(0.92 mmol) of carbon tetrabromide were added at RT. The mixture wasthen stirred at RT for 16 h. For work-up, the mixture was filteredthrough 20 g of kieselguhr, the filter residue was rinsed with ethylacetate and the filtrate was concentrated under reduced pressure. Theresidue was purified by preparative HPLC [Method 19]. This gave 112 mg(42% of theory) of the target compound in a purity of 80% which wereimmediately reacted further.

LC/MS [Method 4]: R_(t)=1.09 min; MS [ESIpos]: m/z=272 and 274 (M+H)⁺.

Example 55A 5-(Bromomethyl)-2-(2,3-dichlorophenyl)-1,3-oxazole

89 mg (0.31 mmol) of the compound from Example 51A were reactedanalogously to the process of Example 54A. This gave, in a purity of87%, 50 mg (52% of theory) of the target compound.

LC/MS [Method 4]: R_(t)=1.15 min; MS [ESIpos]: m/z=308 (M+H)⁺.

Example 56A 2-(Bromomethyl)-5-(2-chlorophenyl)thiophene

200 mg (0.74 mmol) of the compound from Example 52A and 291 mg (1.11mmol) of triphenylphosphine were dissolved in 8 ml of THF, and 367 mg(1.11 mmol) of carbon tetrabromide were added at RT. The mixture wasthen stirred at RT for 16 h. For work-up, the mixture was filteredthrough 20 g of kieselguhr, the filter residue was rinsed with ethylacetate and the filtrate was concentrated under reduced pressure. Theresidue was purified chromatographically on silica gel (mobile phase:cyclohexane/ethyl acetate 10:1, then 5:1). This gave 113 mg ofcontaminated target product (32% pure, 17% of theory) which wereimmediately reacted further.

LC/MS [Method 4]: R_(t)=1.37 min; MS [ESIpos]: m/z=207 (M−HBr)⁺.

Example 57A 2-(Bromomethyl)-5-(2,3-dichlorophenyl)thiophene

89 mg (0.31 mmol) of the compound from Example 53A were reactedanalogously to the process of Example 56A. This gave, in a purity of86%, 70 mg (30% of theory) of the target compound.

LC/MS [Method 4]: R_(t)=1.08 min; MS [ESIpos]: m/z=241 and 243 (M−HBr)⁺.

Example 58A Methyl 2-[2-(trifluoromethyl)phenyl]isonicotinate

Under an atmosphere of argon, 500 mg (2.31 mmol) of methyl2-bromoisonicotinate and 694 mg (3.47 mmol) of2-(trifluoromethyl)phenylboronic acid were dissolved in 10 ml oftoluene. 106 mg (0.12 mmol) of tris(dibenzylideneacetone)dipalladium, 91mg (0.23 mmol) of tri-tert-butylphosphine and 982 mg (4.63 mmol) ofpotassium phosphate were then added, and under argon the mixture washeated to 110° C. for 20 h. For work-up, the mixture was diluted at RTwith 15 ml of ethyl acetate and 15 ml of water, the organic phase wasseparated off and the aqueous phase was extracted two more times with ineach case 15 ml of ethyl acetate. The combined organic phases were driedover magnesium sulfate, filtered and concentrated under reducedpressure. The crude product was purified by chromatography on silica gel(mobile phase: cyclohexane/ethyl acetate 20:1, then 10:1). This gave 498mg (59% of theory) of the target compound in a purity of 77%. A secondproduct fraction of lower purity was purified further according toMethod 19. This gave a further 54 mg (8% of theory) of the targetcompound.

LC/MS [Method 2]: R_(t)=2.21 min; MS [ESIpos]: m/z=282 (M+H)⁺.

Example 59A Methyl 2-(2-chlorophenyl)isonicotinate

500 mg (2.31 mmol) of methyl 2-bromoisonicotinate and 597 mg (3.47 mmol)of 2-chlorophenylboronic acid were reacted with one another analogouslyto the process of Example 58A. This gave 323 mg (56% of theory) of thetarget compound.

LC/MS [Method 3]: R_(t)=1.15 min; MS [ESIpos]: m/z=248 (M+H)⁺.

Example 60A Methyl 2-(2,3-dichlorophenyl)isonicotinate

Under an atmosphere of argon, 250 mg (1.16 mmol) of methyl2-bromoisonicotinate and 331 mg (1.74 mmol) of 2,3-dichlorophenylboronicacid were dissolved in 5 ml of toluene. 53 mg (0.06 mmol) oftris(dibenzylideneacetone)dipalladium, 46 mg (0.12 mmol) of2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl and 491 mg (2.31mmol) of potassium phosphate were then added, and under argon themixture was heated to 110° C. for 20 h. For work-up, the mixture wasdiluted at RT with 15 ml of ethyl acetate and 15 ml of water, theorganic phase was separated off and the aqueous phase was extracted twomore times with in each case 15 ml of ethyl acetate. The combinedorganic phases were dried over magnesium sulfate, filtered andconcentrated under reduced pressure. The crude product was purifiedchromatographically [Method 19]. This gave 138 mg (42% of theory) of thetarget compound in a purity of 87%.

LC/MS [Method 4]: R_(t)=1.13 min; MS [ESIpos]: m/z=282 and 284 (M+H)⁺.

Example 61A {2-[2-(Trifluoromethyl)phenyl]pyridin-4-yl}methanol

432 mg (1.54 mmol) of the compound from Example 58A were dissolved in 10ml of THF, and 1.08 ml (1.08 mmol) of a 1 M solution of lithium aluminumhydride in THF were added at −10° C. After the addition had ended, themixture was stirred at RT for 2 h. For work-up, 4 ml of a saturatedsodium potassium tartrate solution were added at RT, and the mixture wasextracted with 15 ml of ethyl acetate. The organic phase was washed oncewith 10 ml of saturated sodium potassium tartrate solution, dried overmagnesium sulfate, filtered and concentrated under reduced pressure.This gave 497 mg (>100% of theory) of the target compound which werereacted further without any further purification.

LC/MS [Method 2]: R_(t)=1.40 min; MS [ESIpos]: m/z=254 (M+H)⁺.

Example 62A [2-(2-Chlorophenyl)pyridin-4-yl]methanol

323 mg (1.24 mmol) of the compound from Example 59A were reactedanalogously to the process of Example 61A. This gave 303 mg (>100% oftheory) of the target compound which were reacted further without anyfurther purification.

¹H-NMR (400 MHz, DMSO-d₆): δ=4.61 (d, 2H), 5.47 (t, 1H), 7.33-7.37 (m,1H), 7.42-7.48 (m, 2H), 7.53-7.60 (m, 3H), 8.61 (d, 1H).

Example 63A [2-(2,3-Dichlorophenyl)pyridin-4-yl]methanol

138 mg (0.49 mmol) of the compound from Example 60A were reactedanalogously to the process of Example 61A. This gave 132 mg (90% oftheory) of the target compound in a purity of 84% which were reactedfurther without any further purification.

LC/MS [Method 2]: R_(t)=0.78 min; MS [ESIpos]: m/z=254 and 256 (M+H)⁺.

Example 64A 4-(Bromomethyl)-2-[2-(trifluoromethyl)phenyl]pyridine

495 mg (1.96 mmol) of the compound from Example 61A and 615 mg (2.35mmol) of triphenylphosphine were dissolved in 15 ml of THF, and 778 mg(2.35 mmol) of carbon tetrabromide were added at RT. After the additionhad ended, the mixture was stirred at RT for 16 h. For work-up, themixture was filtered through 20 g of kieselguhr and the filtrate wasconcentrated under reduced pressure. The residue was purifiedchromatographically on silica gel (mobile phase: first cyclohexane/ethylacetate 70:30, then ethyl acetate). This gave, in a purity of 90%, 149mg (22% of theory) of the target compound, which were immediatelyreacted further.

LC/MS [Method 3]: R_(t)=1.23 min; MS [ESIpos]: m/z=318 (M+H)⁺.

Example 65A 4-(Bromomethyl)-2-(2-chlorophenyl)pyridine

294 mg (1.34 mmol) of the compound from Example 62A were reactedanalogously to the process of Example 64A. This gave, in a purity of89%, 242 mg (57% of theory) of the target compound, which wereimmediately reacted further.

LC/MS [Method 4]: R_(t)=1.08 min; MS [ESIpos]: m/z=282 and 284 (M+H)⁺.

Example 66A 4-(Bromomethyl)-2-(2,3-dichlorophenyl)pyridine

131 mg (0.52 mmol) of the compound from Example 63A were reactedanalogously to the process of Example 54A. This gave 81 mg (50% oftheory) of the target compound, which were immediately reacted further.

LC/MS [Method 4]: R_(t)=1.08 min; MS [ESIpos]: m/z=316, 318 and 320(M+H)⁺.

Example 67A 4-Methyl-2-[2-(trifluoromethyl)phenyl]pyrimidine

Under an atmosphere of argon, 250 mg (1.95 mmol) of2-chloro-4-methylpyrimidine and 583 mg (2.92 mmol) of2-(trifluoromethyl)phenylboronic acid were dissolved in 8 ml of toluene.89 mg (0.10 mmol) of tris(dibenzylideneacetone)dipalladium, 77 mg (0.19mmol) of 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl and 826mg (3.89 mmol) of potassium phosphate were then added, and under argonthe mixture was heated at 110° C. for 20 h. For work-up, the mixture wasdiluted at RT with 15 ml of ethyl acetate and 15 ml of water, theorganic phase was separated off and the aqueous phase extracted two moretimes with in each case 15 ml of ethyl acetate. The combined organicphases were dried over magnesium sulfate, filtered and concentratedunder reduced pressure. The crude product was purifiedchromatographically on silica gel (mobile phase: cyclohexane/ethylacetate 9:1, then 4:1). This gave 249 mg (54% of theory) of the targetcompound in a purity of 87%.

LC/MS [Method 3]: R_(t)=1.02 min; MS [ESIpos]: m/z=239 (M+H)⁺.

Example 68A 2-(2-Chlorophenyl)-4-methylpyrimidine

250 mg (1.95 mmol) of 2-chloro-4-methylpyrimidine were reactedanalogously to the process of Example 67A. This gave 202 mg (34% oftheory) of the target compound in a purity of 66%.

LC/MS [Method 3]: R_(t)=0.90 min; MS [ESIpos]: m/z=205 (M+H)⁺.

Example 69A 4-Methyl-6-[2-(trifluoromethyl)phenyl]pyrimidine

250 mg (1.95 mmol) of 4-chloro-6-methylpyrimidine were reactedanalogously to the process of Example 67A. This gave 332 mg (70% oftheory) of the target compound.

LC/MS [Method 3]: R_(t)=1.04 min; MS [ESIpos]: m/z=239 (M+H)⁺.

Example 70A 4-Methyl-6-[2-chlorophenyl]pyrimidine

250 mg (1.95 mmol) of 4-chloro-6-methylpyrimidine were reactedanalogously to the process of Example 67A. This gave 191 mg (43% oftheory) of the target compound.

LC/MS [Method 3]: R_(t)=0.99 min; MS [ESIpos]: m/z=205 (M+H)⁺.

Example 71A 4-(2,3-Dichlorophenyl)-6-methylpyrimidine

250 mg (1.95 mmol) of 4-chloro-6-methylpyrimidine were reactedanalogously to the process of Example 67A. This gave 185 mg (40% oftheory) of the target compound.

LC/MS [Method 6]: R_(t)=1.93 min; MS [ESIpos]: m/z=239 and 241 (M+H)⁺.

Example 72A 2-Methyl-5-[2-(trifluoromethyl)phenyl]-1,3,4-thiadiazole

500 mg (1.95 mmol) of 2-bromo-5-methyl-1,3,4-thiadiazole were reactedanalogously to the process of Example 67A. This gave 331 mg (36% oftheory) of the target compound in a purity of 75%.

LC/MS [Method 4]: R_(t)=0.93 min; MS [ESIpos]: m/z=245 (M+H)⁺.

Example 73A 2-(2-Chlorophenyl)-5-methyl-1,3,4-thiadiazole

315 mg (1.76 mmol) of 2-bromo-5-methyl-1,3,4-thiadiazole were reactedanalogously to the process of Example 44A. This gave 155 mg (36% oftheory) of the target compound.

LC/MS [Method 4]: R_(t)=0.92 min; MS [ESIpos]: m/z=211 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=2.82 (s, 3H), 7.52-7.62 (m, 2H), 7.70 (dd,1H), 8.10 (dd, 1H).

Example 74A 2-(2,3-Dichlorophenyl)-5-methyl-1,3,4-thiadiazole

310 mg (1.73 mmol) of 2-bromo-5-methyl-1,3,4-thiadiazole were reactedanalogously to the process of Example 44A. This gave 91 mg (21% oftheory) of the target compound.

LC/MS [Method 6]: R_(t)=2.13 min; MS [ESIpos]: m/z=245 and 247 (M+H)⁺.

Example 75A 5-(2-Chlorophenyl)-2-methyl-1,3-thiazole

756 mg (2.92 mmol) of 5-bromo-2-methyl-1,3-thiazole hydrobromide werereacted analogously to the process of Example 67A. In this reaction,2.49 g (11.68 mmol) of potassium phosphate were used as base. This gave181 mg (30% of theory) of the target compound.

LC/MS [Method 2]: R_(t)=2.21 min; MS [ESIpos]: m/z=210 (M+H)⁺.

Example 76A 2-Methyl-5-[2-(trifluoromethyl)phenyl]-1,3-thiazole

430 mg (1.66 mmol) of 5-bromo-2-methyl-1,3-thiazole hydrobromide werereacted analogously to the process of Example 44A. In this reaction,1.41 g (6.64 mmol) of potassium phosphate were used as base. This gave52 mg (13% of theory) of the target compound.

LC/MS [Method 4]: R_(t)=1.08 min; MS [ESIpos]: m/z=244 (M+H)⁺.

Example 77A 5-(3-Chloro-2-fluorophenyl)-2-methyl-1,3-thiazole

586 mg (2.26 mmol) of 5-bromo-2-methyl-1,3-thiazole hydrobromide werereacted analogously to the process of Example 44A. In this reaction,1.92 g (9.05 mmol) of potassium phosphate were used as base. This gave147 mg (29% of theory) of the target compound.

LC/MS [Method 3]: R_(t)=1.27 min; MS [ESIpos]: m/z=228 (M+H)⁺.

Example 78A 5-[2-Fluoro-3-(trifluoromethyl)phenyl]-2-methyl-1,3-thiazole

350 mg (1.35 mmol) of 5-bromo-2-methyl-1,3-thiazole hydrobromide werereacted analogously to the process of Example 44A. In this reaction,1.15 g (5.41 mmol) of potassium phosphate were used as base. Thereaction time was 2 h. This gave 89 mg (25% of theory) of the targetcompound.

LC/MS [Method 4]: R_(t)=1.12 min; MS [ESIpos]: m/z=262 (M+H)⁺.

Example 79A 5-(2-Chlorophenyl)-2-methyl-4-(trifluoromethyl)-1,3-thiazole

635 mg (1.94 mmol) of 5-bromo-2-methyl-4-(trifluoromethyl)-1,3-thiazolehydrobromide were reacted analogously to the process of Example 44A. Inthis reaction, 1.15 g (5.41 mmol) of potassium phosphate were used asbase. This gave 142 mg (26% of theory) of the target compound.

LC/MS [Method 3]: R_(t)=1.34 min; MS [ESIpos]: m/z=278 (M+H)⁺.

Example 80A 4-(Bromomethyl)-2-[2-(trifluoromethyl)phenyl]pyrimidine

247 mg (1.04 mmol) of the compound from Example 67A together with 185 mg(1.04 mmol) of N-bromosuccinimide and 17 mg (0.10 mmol) of2,2′-azobis-2-methylpropanenitrile in 3 ml of carbon tetrachloride wereheated under reflux for 18 h. For work-up, the reaction mixture wascooled to RT, and 10 ml of dichloromethane were added. The mixture waswashed with 5 ml of water, and the aqueous phase was re-extracted twicewith in each case 5 ml of dichloromethane. The combined organic phaseswere dried over magnesium sulfate, filtered and concentrated underreduced pressure. The crude product was briefly dried under high vacuumand reacted further without further purification. This gave 303 mg ofproduct which contained the target compound in a purity of 20%(corresponds to 20% of theory). The main component of the crude productwas unreacted starting material (Example 67A).

LC/MS [Method 4]: R_(t)=1.02 min; MS [ESIpos]: m/z=317 and 319 (M+H)⁺.

Example 81A 4-(Bromomethyl)-2-(2-chlorophenyl)pyrimidine

200 mg (0.98 mmol) of the compound from Example 68A were reactedanalogously to the process of Example 80A. This gave 259 mg (19% oftheory) of the target compound in a purity of about 20%. The maincomponent of the crude product was unreacted starting material (Example68A).

LC/MS [Method 4]: R_(t)=1.00 min; MS [ESIpos]: m/z=283 and 285 (M+H)⁺.

Example 82A 4-(Bromomethyl)-6-[2-(trifluoromethyl)phenyl]pyrimidine

332 mg (1.39 mmol) of the compound from Example 69A were reactedanalogously to the process of Example 80A. The crude product waspurified chromatographically [Method 19]. This gave 37 mg (8% of theory)of the target compound.

LC/MS [Method 3]: R_(t)=1.19 min; MS [ESIpos]: m/z=317 and 319 (M+H)⁺.

Example 83A 4-(Bromomethyl)-6-[2-chlorophenyl]pyrimidine

191 mg (0.93 mmol) of the compound from Example 70A were reactedanalogously to the process of Example 80A. The crude product waspurified chromatographically [Method 19]. This gave 27 mg (10% oftheory) of the target compound.

LC/MS [Method 3]: R_(t)=1.15 min; MS [ESIpos]: m/z=283 and 285 (M+H)⁺.

Example 84A 4-(Bromomethyl)-6-(2,3-dichlorophenyl)pyrimidine

185 mg (0.93 mmol) of the compound from Example 71A were reactedanalogously to the process of Example 80A. The crude product waspurified chromatographically [Method 19]. This gave 23 mg (9% of theory)of the target compound.

LC/MS [Method 6]: R_(t)=2.32 min; MS [ESIpos]: m/z=317, 319 and 321(M+H)⁺.

Example 85A2-(Bromomethyl)-5-[2-(trifluoromethyl)phenyl]-1,3,4-thiadiazole

172 mg (0.70 mmol) of the compound from Example 72A together with 251 mg(1.41 mmol) of N-bromosuccinimide and 12 mg (0.07 mmol) of2,2′-azobis-2-methylpropanenitrile in 5 ml of carbon tetrachloride wereheated under reflux for 8 h. For work-up, the reaction mixture wascooled to RT, and 10 ml of dichloromethane were added. The mixture waswashed with 5 ml of water, and the aqueous phase was re-extracted twicewith in each case 5 ml of dichloromethane. The combined organic phaseswere dried over magnesium sulfate, filtered and concentrated underreduced pressure. The crude product was purified chromatographically[Method 19]. This gave 33 mg (15% of theory) of the target compound.

LC/MS [Method 4]: R_(t)=1.05 min; MS [ESIpos]: m/z=323 and 325 (M+H)⁺.

Example 86A 2-(Bromomethyl)-5-(2-chlorophenyl)-1,3,4-thiadiazole

185 mg (0.88 mmol) of the compound from Example 73A were reactedanalogously to the process of Example 85A. The crude product waspurified chromatographically [Method 19]. This gave 31 mg (12% oftheory) of the target compound.

LC/MS [Method 6]: R_(t)=2.21 min; MS [ESIpos]: m/z=289 and 291 (M+H)⁺.

Example 87A 2-(Bromomethyl)-5-(2,3-dichlorophenyl)-1,3,4-thiadiazole

91 mg (0.37 mmol) of the compound from Example 74A were reactedanalogously to the process of Example 85A. The crude product waspurified chromatographically [Method 19]. This gave 38 mg (32% oftheory) of the target compound.

LC/MS [Method 3]: R_(t)=1.30 min; MS [ESIpos]: m/z=323, 325 and 327(M+H)⁺.

Example 88A 2-(Bromomethyl)-5-(2-chlorophenyl)-1,3-thiazole

180 mg (0.86 mmol) of the compound from Example 75A together with 229 mg(1.29 mmol) of N-bromosuccinimide and 14 mg (0.09 mmol) of2,2′-azobis-2-methylpropanenitrile in 5 ml of carbon tetrachloride wereheated under reflux for 8 h. For work-up, the reaction mixture wascooled to RT, and 10 ml of dichloromethane were added. The mixture waswashed with 5 ml of water, and the aqueous phase was re-extracted twicewith in each case 5 ml of dichloromethane. The combined organic phaseswere dried over magnesium sulfate, filtered and concentrated underreduced pressure. The crude product was purified chromatographically[Method 19]. This gave 66 mg (27% of theory) of the target compound.

LC/MS [Method 2]: R_(t)=2.42 min; MS [ESIpos]: m/z=288 and 290 (M+H)⁺.

Example 89A 2-(Bromomethyl)-5-[2-(trifluoromethyl)phenyl]-1,3-thiazole

110 mg (0.45 mmol) of the compound from Example 76A were reactedanalogously to the process of Example 88A. The crude product waspurified chromatographically [Method 19]. This gave 40 mg (27% oftheory) of the target compound.

LC/MS [Method 4]: R_(t)=1.17 min; MS [ESIpos]: m/z=322 and 324 (M+H)⁺.

Example 90A 2-(Bromomethyl)-5-(3-chloro-2-fluorophenyl)-1,3-thiazole

142 mg (0.62 mmol) of the compound from Example 77A were reactedanalogously to the process of Example 88A. The crude product waspurified chromatographically [Method 19]. This gave 70 mg (37% oftheory) of the target compound.

LC/MS [Method 4]: R_(t)=1.21 min; MS [ESIpos]: m/z=306 and 308 (M+H)⁺.

Example 91A2-(Bromomethyl)-5-[2-fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazole

120 mg (0.46 mmol) of the compound from Example 78A were reactedanalogously to the process of Example 88A. The crude product waspurified chromatographically [Method 19]. This gave 60 mg (38% oftheory) of the target compound.

LC/MS [Method 4]: R_(t)=1.20 min; MS [ESIpos]: m/z=340 and 342 (M+H)⁺.

Example 92A2-(Bromomethyl)-5-(2-chlorophenyl)-4-(trifluoromethyl)-1,3-thiazole

140 mg (0.50 mmol) of the compound from Example 79A were reactedanalogously to the process of Example 88A. The crude product waspurified chromatographically [Method 19]. This gave 49 mg (27% oftheory) of the target compound.

LC/MS [Method 4]: R_(t)=1.27 min; MS [ESIpos]: m/z=356 and 358 (M+H)⁺.

Example 93A5-(4-Chlorophenyl)-4-cyclopropyl-2-(1H-1,2,4-triazol-5-ylsulfonyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

300 mg (1.27 mmol) of5-(4-chlorophenyl)-4-cyclopropyl-2,4-dihydro-3H-1,2,4-triazol-3-one[preparation according to WO 2007/134862 Example 36A] were dissolved in10 ml of THF, and 143 mg (1.27 mmol) of potassium tert-butoxide wereadded at −78° C. Over a period of 30 min, the reaction mixture waswarmed to RT, and the mixture was stirred at this temperature for afurther 20 min. The mixture was then once more cooled to −78° C., and213 mg (1.27 mmol) of 1H-1,2,4-triazole-5-sulfonyl chloride, dissolvedin 5 ml of THF, were added. Over a period of 30 min, the reactionmixture was warmed to RT, and the mixture was stirred at thistemperature for a further 20 h. For work-up, 10 ml of water were added.The mixture was extracted twice with in each case 15 ml of ethylacetate. The combined organic phases were dried over sodium sulfate,filtered and concentrated under reduced pressure. The crude product waspurified chromatographically [Method 19]. This gave 136 mg (29% oftheory) of the target compound.

LC/MS [Method 5]: R_(t)=1.91 min; m/z=367 (M+H)⁺.

Example 94A5-(4-Chlorophenyl)-4-(4-methoxybenzyl)-2-(1H-1,2,4-triazol-5-ylsulfonyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

529 mg (1.68 mmol) of5-(4-chlorophenyl)-4-(4-methoxybenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one[preparation according to WO 2007/134862 Example 55A] were dissolved in10 ml of acetonitrile, and 1.09 g (3.35 mmol) of cesium carbonate and281 mg (1.68 mmol) of 1H-1,2,4-triazole-5-sulfonyl chloride, dissolvedin 5 ml of acetonitrile, were added successively. The reaction mixturewas stirred at RT for 90 min. For work-up, 10 g of silica gel were addedand the solvent was removed under reduced pressure. The crude product,adsorbed on silica gel, was purified by chromatography on silica gel(mobile phase: first ethyl acetate, then dichloromethane/methanol90:10→80:20). This gave 268 mg (32% of theory) of the target compound.

LC/MS [Method 5]: R_(t)=2.21 min; m/z=447 (M+H)⁺.

Example 95A5-(4-Chlorophenyl)-2-({1-[2-(trifluoromethyl)benzyl]-1H-1,2,4-triazol-5-yl}sulfonyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

230 mg (0.38 mmol) of the compound from Example 116 were dissolved in 5ml of acetonitrile, and 417 mg (0.76 mmol) of ammonium cerium(IV)nitrate, dissolved in 5 ml of water, were added. The mixture was thenstirred at 70° C. for 20 h. For work-up, the mixture was concentratedunder reduced pressure, and the residue was taken up in 15 ml of waterand extracted twice with in each case 15 ml of ethyl acetate. Thecombined organic phases were dried over magnesium sulfate, filtered andconcentrated under reduced pressure. The crude product was purified bychromatography on silica gel (mobile phase: dichloromethane/methanol99:1→90:10). This gave 130 mg (70% of theory) of the target compound.

LC/MS [Method 3]: R_(t)=1.22 min; m/z=485 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=5.59 (s, 2H), 7.38 (d, 1H), 7.44 (d, 2H),7.45-7.55 (m, 2H), 7.70 (d, 1H), 7.81 (d, 2H), 8.12 (s, 1H).

Example 96A4-Allyl-5-(4-chlorophenyl)-2-[(5-methyl-1H-imidazol-4-yl)methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

100 mg (0.89 mmol) of 4-hydroxymethyl-5-methyl-1H-imidazole, 252 mg(1.07 mmol) of the compound from Example 12A and 370 mg (2.68 mmol) ofpotassium carbonate were dissolved in 4.5 ml of DMF and 4.5 ml of water,and the mixture was stirred in a microwave oven at 200° C. for 75 minAfter cooling to RT, for work-up, the mixture was diluted with 10 ml ofwater and extracted twice with in each case 15 ml of ethyl acetate. Thecombined organic phases were dried over sodium sulfate, filtered andconcentrated under reduced pressure. The crude product was purified bychromatography on silica gel (mobile phase: first cyclohexane/ethylacetate 1:1, then dichloromethane/methanol 10:1). This gave 153 mg (52%of theory) of the target compound in a purity of 73%.

LC/MS [Method 3]: R_(t)=0.82 min; MS [ESIpos]: m/z=330 (M+H)⁺.

Example 97A5-(4-Chlorophenyl)-4-cyclopropyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

Analogously to the compound in Example 96A, 181 mg (1.62 mmol) of4-hydroxymethyl-5-methyl-1H-imidazole, 381 mg (1.62 mmol) of5-(4-chlorophenyl)-4-cyclopropyl-2,4-dihydro-3H-1,2,4-triazol-3-one[preparation according to WO 2007/134862 Example 36A] and 670 mg (4.85mmol) of potassium carbonate were reacted with one another. This gave180 mg (47% of theory) of the target compound in a purity of 76%.

LC/MS [Method 1]: R_(t)=0.82 min; MS [ESIpos]: m/z=330 (M+H)⁺.

Example 98A Ethyl bromo[2-(trifluoromethyl)phenyl]acetate

585 mg (3.89 mmol) of sodium bromate were initially charged in 2 ml ofwater, and 300 mg (1.29 mmol) of ethyl 2-(trifluoromethyl)phenylacetate,dissolved in 2.5 ml of ethyl acetate, were added at RT. A solution of403 mg (3.89 mmol) of sodium bisulfite in 3.8 ml of water was then addedslowly. The mixture was stirred at RT for 18 h. 5 ml of 10% strengthaqueous sodium dithionite solution were then added. The mixture wasextracted with 15 ml of ethyl acetate, and the organic phase was washedin each case once with 5 ml of 10% strength sodium dithionite solutionand 5 ml of saturated sodium chloride solution. The organic phase wasdried over sodium sulfate, filtered and concentrated under reducedpressure. The crude product was purified by chromatography on silica gel(mobile phase: cyclohexane/ethyl acetate 20:1, then 10:1). This gave 186mg of a mixture consisting of the title compound and the startingmaterial ethyl 2-(trifluoromethyl)phenylacetate (ratio 16:84 accordingto GC/MS [Method 20]). This mixture was once more reacted with 362 mg(2.40 mmol) of sodium bromate and 250 mg (2.40 mmol) of sodium bisulfiteaccording to the procedure described above. Work-up gave a mixture of31% title compound and 69% ethyl 2-(trifluoromethyl)phenylacetate, whichwas reacted further without any further purification.

GC/MS [Method 20]: R_(t)=4.28 min; MS [ESIpos]: m/z=237 (M-CO₂C₂H₅)⁺.

Example 99A2-(2-Bromobenzyl)-5-(4-chlorophenyl)-4-cyclopropyl-2,4-dihydro-3H-1,2,4-triazol-3-one

1.04 g (4.41 mmol) of5-(4-chlorophenyl)-4-cyclopropyl-2,4-dihydro-3H-1,2,4-triazol-3-one[preparation according to WO 2007/134862 Example 36A] and 2.16 g (6.62mmol) of cesium carbonate were suspended in 35 ml of acetonitrile, and1.32 g (5.30 mmol) of 2-bromobenzyl bromide were added. The mixture wasstirred under reflux for 18 h. The precipitated solid was then filteredoff and the filtrate was concentrated under reduced pressure. The solidthat remained was stirred in about 50 ml of diethyl ether and thenfiltered off and washed with a little diethyl ether. Drying underreduced pressure gave 1.05 g (59% of theory) of the target compound as awhite solid.

LC/MS [Method 4]: R_(t)=1.19 m; MS [ESIpos]: m/z=404 and 406 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=0.58-0.65 (m, 2H), 0.85-0.93 (m, 2H), 3.20(tt, 1H), 4.99 (s, 2H), 7.18-7.30 (m, 2H), 7.34-7.41 (m, 1H), 7.56-7.61(m, 2H), 7.65 (d, 1H), 7.80 (d, 2H).

Example 100A2-(5-Bromo-2-fluorobenzyl)-5-(4-chlorophenyl)-4-cyclopropyl-2,4-dihydro-3H-1,2,4-triazol-3-one

300 mg (1.27 mmol) of5-(4-chlorophenyl)-4-cyclopropyl-2,4-dihydro-3H-1,2,4-triazol-3-one[preparation according to WO 2007/134862 Example 36A] and 622 mg (1.91mmol) of cesium carbonate were suspended in 5 ml of acetonitrile, and536 mg (1.40 mmol) of 4-bromo-2-(bromomethyl)-1-fluorobenzene wereadded. The mixture was stirred under reflux for 18 h. The precipitatedsolid was then filtered off and the filtrate was concentrated underreduced pressure to a volume of about 1.5 ml. After addition of 0.5 mlof 1 N hydrochloric acid, the mixture was directly purifiedchromatographically [Method 19]. This gave 427 mg (56% of theory) of thetarget compound in a purity of 71%.

LC/MS [Method 4]: R_(t)=1.23 min; MS [ESIpos]: m/z=422 and 424 (M+H)⁺.

Example 101A2-(3-Bromobenzyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

400 mg (1.30 mmol) of the compound from Example 4A and 635 mg (1.95mmol) of cesium carbonate were suspended in 3 ml of acetonitrile, and357 mg (1.43 mmol) of 3-bromobenzyl bromide were added. The mixture wasstirred under reflux for 20 h. The precipitated solid was then filteredoff, and the filtrate was concentrated under reduced pressure to avolume of about 1.5 ml and directly purified chromatographically [Method19]. This gave 507 mg (82% of theory) of the target compound.

LC/MS [Method 4]: R_(t)=1.21 min; MS [ESIpos]: m/z=476 and 478 (M+H)⁺.

Example 102A2-(3-Bromobenzyl)-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

80 mg (0.26 mmol) of the compound from Example 5A were reactedanalogously to the preparation of Example 101A. This gave 95 mg (76% oftheory) of the target compound.

LC/MS [Method 4]: R_(t)=1.21 min; MS [ESIpos]: m/z=476 and 478 (M+H)⁺.

Example 103A2-(3-Bromo-5-fluorobenzyl)-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

219 mg (0.71 mmol) of the compound from Example 5A and 191 mg (0.71mmol) of 1-bromo-3-(bromomethyl)-5-fluorobenzene were reactedanalogously to the preparation of Example 101A. This gave 181 mg (51% oftheory) of the target compound.

LC/MS [Method 4]: R_(t)=1.24 min; MS [ESIpos]: m/z=494 and 496 (M+H)⁺.

Example 104A Methyl4-bromo-2-{[3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]methyl}benzoate

450 mg (1.30 mmol) of the compound from Example 4A and 715 mg (2.19mmol) of cesium carbonate were suspended in 6 ml of acetonitrile, and708 mg (1.61 mmol) of methyl 4-bromo-2-(bromomethyl)benzoate were added.The mixture was stirred under reflux for 20 h. The precipitated solidwas filtered off and the filtrate was concentrated under reducedpressure to a volume of about 1.5 ml. After addition of 1 ml of 1 Nhydrochloric acid, the mixture was directly purified chromatographically[Method 19]. This gave 545 mg (64% of theory) of the target compound ina purity of 92%.

LC/MS [Method 4]: R_(t)=1.24 min; MS [ESIpos]: m/z=534 and 536 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.81-3.90 (m, 4H), 4.01 (dd, 1H), 4.24-4.34(m, 1H), 5.29-5.40 (m, 2H), 6.89 (d, 1H), 7.42 (d, 1H), 7.64 (d, 2H),7.69 (dd, 1H), 7.74 (d, 2H), 7.84 (d, 1H).

Example 105A Methyl4-bromo-2-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)benzoate

515 mg (1.67 mmol) of the compound from Example 5A and 818 mg (2.51mmol) of cesium carbonate were suspended in 10 ml of acetonitrile, and810 mg (1.84 mmol) of methyl 4-bromo-2-(bromomethyl)benzoate were added.The mixture was stirred under reflux for 3 h. After cooling to RT, 15 mlof water were added and the mixture was extracted three times with ineach case 10 ml of ethyl acetate. The combined organic phases were driedover sodium sulfate, filtered and concentrated under reduced pressure.The residue was purified chromatographically [Method 19]. This gave 455mg (51% of theory) of the target compound.

LC/MS [Method 4]: R_(t)=1.21 min; MS [ESIpos]: m/z=534 and 536 (M+H)⁺.

Example 106A Methyl 5-methyl-2′-(trifluoromethyl)biphenyl-2-carboxylate

Under argon, 500 mg (2.18 mmol) of methyl 2-bromo-4-methylbenzoatetogether with 655 mg (3.27 mmol) of 2-(trifluoromethyl)phenylboronicacid were dissolved in 10 ml of toluene, and 86 mg (0.22 mmol) of2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl, 100 mg (0.11mmol) of tris(dibenzylideneacetone)dipalladium and 927 mg (4.37 mmol) ofpotassium phosphate were added successively. The mixture was heated to110° C. and stirred at this temperature for 20 h. For work-up, thereaction mixture was allowed to cool to RT and diluted with 20 ml ofethyl acetate and 20 ml of water. After phase separation, the aqueousphase was extracted two more times with in each case 20 ml of ethylacetate. The combined organic phases were dried over magnesium sulfate,filtered and concentrated under reduced pressure. The residue waspurified by chromatography on silica gel (mobile phase: firstcyclohexane/ethyl acetate 30:1, then 20:1). This gave 597 mg (86% oftheory) of the target compound.

GC/MS [Method 20]: R_(t)=5.55 min; MS [EIpos]: m/z=294 (M)⁺.

Example 107A Methyl 2′-chloro-5-methylbiphenyl-2-carboxylate

500 mg (2.18 mmol) of methyl 2-bromo-4-methylbenzoate and 512 mg (3.27mmol) of 2-chlorophenylboronic acid were reacted analogously to thepreparation of Example 107A. This gave 275 mg (48% of theory) of thetarget compound.

LC/MS [Method 4]: R_(t)=1.22 min; MS [ESIpos]: m/z=261 (M+H)⁺.

Example 108A Methyl5-(bromomethyl)-2′-(trifluoromethyl)biphenyl-2-carboxylate

590 mg (2.01 mmol) of the compound from Example 107A, 357 mg (2.01 mmol)of N-bromosuccinimide and 33 mg (0.20 mmol) of2,2′-azobis-2-methylpropanenitrile in 8 ml of carbon tetrachloride wereheated under reflux for 16 h. After cooling to RT, the mixture wasdiluted with 10 ml of dichloromethane and washed with 10 ml of water.The organic phase was dried over magnesium sulfate, filtered andconcentrated under reduced pressure. The crude product was purifiedchromatographically [Method 19]. This gave 346 mg (30% of theory) of thetarget compound in a purity of 64% which were immediately reactedfurther.

LC/MS [Method 4]: R_(t)=1.27 min; MS [DCI]: m/z=390 and 392 (M+NH₄)⁺.

Example 109A Methyl 5-(bromomethyl)-2′-chlorobiphenyl-2-carboxylate

270 mg (1.04 mmol) of the compound from Example 108A andN-bromosuccinimide were reacted analogously to the preparation ofExample 109A. This gave 232 mg (66% of theory) of the target compoundwhich were immediately reacted further.

LC/MS [Method 4]: R_(t)=1.22 min; MS [DCI]: m/z=356 and 358 (M+NH₄)⁺.

Example 110A Dimethyl 2′-chlorobiphenyl-3,5-dicarboxylate

Under argon, 500 mg (1.83 mmol) of dimethyl 5-bromoisophthalate togetherwith 429 mg (2.75 mmol) of 2-chlorophenylboronic acid were dissolved in8 ml of toluene, and 72 mg (0.18 mmol) of2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl, 84 mg (0.09mmol) of tris(dibenzylideneacetone)dipalladium and 777 mg (3.66 mmol) ofpotassium phosphate were added successively. The mixture was heated to110° C. and stirred at this temperature for 20 h. For work-up, thereaction mixture was allowed to cool to RT and diluted with 20 ml ofethyl acetate. The solid was filtered off with suction and the residuewas washed three times with in each case 10 ml of ethyl acetate. Thecombined filtrates were washed twice with in each case 10 ml of water.The organic phase was dried over magnesium sulfate, filtered andconcentrated under reduced pressure. The residue was purifiedchromatographically [Method 19]. This gave 305 mg (55% of theory) of thetarget compound.

LC/MS [Method 4]: R_(t)=1.24 min; MS [EIpos]: m/z=305 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.92 (s, 6H), 7.46-7.55 (m, 3H), 7.60-7.68(m, 1H), 8.23 (d, 2H), 8.52 (t, 1H).

Example 111A Methyl 2′-chloro-5-(hydroxymethyl)biphenyl-3-carboxylate

305 mg (1.00 mmol) of the compound from Example 110A were dissolved in 6ml of THF, and 0.5 ml (0.50 mmol) of a 1 M solution of lithium aluminumhydride in THF was added at −10° C. The reaction mixture was thenstirred at RT for 1 h. For work-up, 3 ml of saturated aqueous sodiumpotassium tartrate solution were added at RT, and the mixture wasextracted with 15 ml of ethyl acetate. The organic phase was washed oncewith 10 ml of saturated sodium potassium tartrate solution, dried overmagnesium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified chromatographically [Method 19]. This gave 189 mg(68% of theory) of the target compound.

LC/MS [Method 4]: R_(t)=1.03 min; MS [ESIpos]: m/z=277 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.88 (s, 3H), 4.63 (d, 2H), 5.43 (t, 1H),7.43-7.47 (m, 3H), 7.58-7.62 (m, 1H), 7.62-7.64 (m, 1H), 7.84-7.87 (m,1H), 7.97-8.00 (m, 1H).

Example 112A Methyl 5-(bromomethyl)-2′-chlorobiphenyl-3-carboxylate

187 mg (0.68 mmol) of the compound from Example 111A and 266 mg (1.01mmol) of triphenylphosphine were dissolved in 6 ml of THF, and 336 mg(1.01 mmol) of carbon tetrabromide were added at RT. The mixture wasthen stirred at RT for 16 h. For work-up, the mixture was filteredthrough 20 g of kieselguhr, the filter cake was washed with ethylacetate and the filtrate was concentrated under reduced pressure. Theresidue was purified chromatographically on silica gel (mobile phase:cyclohexane/ethyl acetate 7:3). This gave 275 mg (>100% of theory) ofthe target compound, which were immediately reacted further.

¹H-NMR (400 MHz, DMSO-d₆): δ=3.89 (s, 3H), 4.86 (s, 2H), 7.44-7.50 (m,3H), 7.58-7.64 (m, 1H), 7.80-7.82 (m, 1H), 7.90-7.92 (m, 1H), 8.08-8.11(m, 1H).

Example 113A and Example 114A Methyl5-bromo-2′-chlorobiphenyl-3-carboxylate and methyl2,2″-dichloro-1,1′:3′,1″-terphenyl-5′-carboxylate

Under argon, 60 mg (0.05 mmol) oftetrakis(triphenylphosphine)palladium(0) were added to 300 mg (1.02mmol) of methyl 3,5-dibromobenzoate in 6 ml of dioxane. The mixture washeated to 110° C., and 1.0 ml (2.00 mmol) of 2 M aqueous sodiumcarbonate solution and 239 mg (1.53 mmol) of 2-chlorophenylboronic acid,dissolved in 1 ml of dioxane, were added successively. The mixture wasthen stirred at 110° C. for 1 h. For work-up, the reaction mixture wasallowed to cool to RT and diluted with 20 ml of ethyl acetate and 20 mlof water. After phase separation, the aqueous phase was extracted twomore times with in each case 20 ml of ethyl acetate. The combinedorganic phases were dried over magnesium sulfate, filtered andconcentrated under reduced pressure. The residue was separated into thecomponents by preparative HPLC [Method 19]. This gave 142 mg (43% oftheory) of methyl 5-bromo-2′-chlorobiphenyl-3-carboxylate (Example 113A)and 166 mg (46% of theory) of methyl2,2″-dichloro-1,1′:3′,1″-terphenyl-5′-carboxylate (Example 114A) asreaction products.

Example 113A

GC/MS [Method 20]: R_(t)=7.50 min; MS [ESIpos]: m/z=324 and 326 (M)⁺.

Example 114A

GC/MS [Method 20]: R_(t)=10.26 min; MS [ESIpos]: m/z=356 and 358 (M)⁺.

Example 115A (5-Bromo-2′-chlorobiphenyl-3-yl)methanol

170 mg (0.52 mmol) of the compound from Example 113A were dissolved in 6ml of THF, and 0.37 ml (0.37 mmol) of a 1 M solution of lithium aluminumhydride in THF was added at −10° C. The mixture was then stirred at RTfor 1 h. For work-up, 4 ml of saturated aqueous sodium potassiumtartrate solution were added at RT, and the mixture was extracted with15 ml of ethyl acetate. The organic phase was washed once with 10 ml ofsaturated sodium potassium tartrate solution, dried over magnesiumsulfate, filtered and concentrated under reduced pressure. This gave 177mg (>100% of theory) of the target compound.

LC/MS [Method 2]: R_(t)=2.39 min

GC/MS [Method 20]: R_(t)=7.67 min; MS [ESIpos]: m/z=296 and 298 (M)⁺.

Example 116A (2,2″-Dichloro-1,1′:3′,1″-terphenyl-5′-yl)methanol

311 mg (0.87 mmol) of the compound from Example 114A were reactedanalogously to the preparation of Example 115A. This gave 283 mg (91% oftheory) of the target compound.

LC/MS [Method 2]: R_(t)=2.63 min

MS [DCI]: m/z=346 (M+NH₄)⁺.

Example 117A 3′-Bromo-5′-(bromomethyl)-2-chlorobiphenyl

177 mg (0.60 mmol) of the compound from Example 115A and 187 mg (0.71mmol) of triphenylphosphine were dissolved in 4 ml of THF, and 237 mg(0.71 mmol) of carbon tetrabromide were added at RT. The mixture wasthen stirred at RT for 16 h. For work-up, the mixture was filteredthrough 20 g of kieselguhr and the filtrate was concentrated underreduced pressure. The residue was purified chromatographically [Method19]. This gave, in a purity of 79%, 129 mg (60% of theory) of the targetcompound, which were immediately reacted further.

LC/MS [Method 4]: R_(t)=1.41 min

Example 118A 5′-(Bromomethyl)-2,2″-dichloro-1,1′:3′,1″-terphenyl

280 mg (0.85 mmol) of the compound from Example 116A were reactedanalogously to the preparation of Example 117A. Purification of thecrude product was carried out by chromatography on silica gel (mobilephase: cyclohexane/ethyl acetate 10:1). This gave 300 mg (76% of theory)of the target compound.

GC/MS [Method 20]: R_(t)=10.64 min; MS [ESIpos]: m/z=390, 392 and 394(M)⁺

MS [DCI]: m/z=408, 410 and 412 (M+NH₄)⁺.

Example 119A2-[(3-Bromophenyl)sulfonyl]-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

360 mg (1.17 mmol) of the compound from Example 5A were dissolved in 10ml of THF and, at 0° C., 94 mg (2.34 mmol) of sodium hydride (60%strength dispersion in mineral oil) were added. After 20 min, 299 mg(1.17 mmol) of 3-bromobenzenesulfonyl chloride were added, and themixture was stirred at 0° C. for 1 h. For work-up, 10 ml of water wereadded and the mixture was extracted twice with in each case 15 ml ofethyl acetate. The combined organic phases were dried over sodiumsulfate, filtered and concentrated under reduced pressure. The crudeproduct was purified by chromatography on silica gel (mobile phase:cyclohexane/ethyl acetate 8:1, then 1:1). This gave 181 mg (27% oftheory) of the target compound.

LC/MS [Method 3]: R_(t)=1.33 min; MS [ESIpos]: m/z=526 and 528 (M+H)⁺.

Example 120A2-[(3-Bromophenyl)sulfonyl]-5-(4-chlorophenyl)-4-[(1E)-3,3,3-trifluoroprop-1-en-1-yl]-2,4-dihydro-3H-1,2,4-triazol-3-one

500 mg (1.63 mmol) of the compound from Example 5A were dissolved in 10ml of acetonitrile, and 449 mg (3.25 mmol) of potassium carbonate and415 mg (1.63 mmol) of 3-bromobenzenesulfonyl chloride were added. Themixture was heated under reflux for 2 h. For work-up, 10 ml of waterwere added and the mixture was extracted twice with in each case 15 mlof ethyl acetate. The combined organic phases were dried over sodiumsulfate, filtered and concentrated under reduced pressure. The crudeproduct was purified by chromatography on silica gel (mobile phase:cyclohexane/ethyl acetate 8:1→5:1→1:1). This gave 285 mg (34% of theory)of the target compound.

LC/MS [Method 4]: R_(t)=1.31 min; MS [ESIpos]: m/z=508 and 510 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=6.72 (dq, 1H), 6.89-6.95 (m, 1H), 7.62-7.66(m, 2H), 7.67-7.73 (m, 3H), 8.05-8.11 (m, 2H), 8.14 (t, 1H).

Example 121A5-(4-Chlorophenyl)-4-cyclopropyl-2-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

7 ml of a 37% strength solution of formaldehyde in water were added to1000 mg (4.24 mmol) of5-(4-chlorophenyl)-4-cyclopropyl-2,4-dihydro-3H-1,2,4-triazol-3-one[preparation according to WO 2007/134862 Example 36A], and the mixturewas stirred at RT for 20 h. The precipitated solid was filtered off withsuction and washed with water. Drying under high vacuum gave 878 mg (62%of theory) of the target compound.

¹H-NMR (400 MHz, CDCl₃): δ=0.71-0.78 (m, 2H), 0.98-1.06 (m, 2H), 2.98(m, 1H), 5.34 (s, 2H), 7.46 (d, 2H), 7.69 (d, 2H).

Example 122A2-(Chloromethyl)-5-(4-chlorophenyl)-4-cyclopropyl-2,4-dihydro-3H-1,2,4-triazol-3-one

875 mg (3.29 mmol) of the compound from Example 121A were suspended in 3ml of dichloromethane, and a drop of DMF and 288 μl (3.95 mmol) ofthionyl chloride were added. The mixture was stirred at RT for 3 h. Forwork-up, 5 ml of saturated aqueous sodium bicarbonate solution wereadded. The mixture was extracted once with 10 ml of tert-butyl methylether. The organic phase was washed once with 5 ml of water, dried oversodium sulfate, filtered and concentrated under reduced pressure. Dryingof the residue under high vacuum gave 803 mg (86% of theory) of thetarget compound.

¹H-NMR (400 MHz, CDCl₃): δ=0.74-0.80 (m, 2H), 1.00-1.06 (m, 2H), 2.98(m, 1H), 5.66 (s, 2H), 7.48 (d, 2H), 7.72 (d, 2H).

WORKING EXAMPLES Example 15-(5-Chlorothiophen-2-yl)-4-(2-fluorobenzyl)-2-({3-[2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

Under argon, 95 mg (0.18 mmol) ofbenzotriazol-1-yloxy-tris(pyrrolidino)phosphonium hexafluorophosphatewere added to a solution of 56 mg (0.15 mmol) of[3-(5-chloro-2-thienyl)-4-(2-fluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]aceticacid [preparation according to WO 2007/134862 Example 154A] and 32 μl(0.18 mmol) of N,N-diisopropylethylamine in 1.5 ml of dry DMF. After 20min of stirring, 34 mg (0.17 mmol) ofN′-hydroxy-2-(trifluoromethyl)benzenecarboximidamide were added. Themixture was then stirred at RT for 16 h. For work-up, 10 ml of waterwere added and the mixture was extracted three times with in each case10 ml of ethyl acetate. The combined organic phases were washed with ineach case 10 ml of water and saturated sodium chloride solution,filtered through Extrelut and concentrated under reduced pressure. Theresidue was dissolved in 2 ml of DMF and stirred in a microwave oven at250° C. for 15 min After cooling, the solvent was removed under reducedpressure on a rotary evaporator and the crude product waschromatographed on silica gel (mobile phase: cyclohexane/ethyl acetate4:1). This gave 60 mg (72% of theory) of the target compound as a yellowresin.

LC/MS [Method 9]: R_(t)=4.25 min; MS [ESIpos]: m/z=536 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=5.15 (s, 2H), 5.42 (s, 2H), 6.35 (d, 2H),6.93 (d, 2H), 7.01-7.29 (m, 3H), 7.23-7.34 (m, 1H), 7.60-7.70 (m, 2H),7.76-7.89 (m, 2H).

Example 22-{[3-(2-Chlorobenzyl)-1,2,4-oxadiazol-5-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

50 mg (0.13 mmol) of the compound from Example 7A were dissolved in 2 mlof toluene, 51 mg (0.28 mmol) of(1Z)-2-(2-chlorophenyl)-N′-hydroxyethaneimidamide and 38 mg (0.28 mmol)of potassium carbonate were added and the mixture was heated underreflux for 6 h. For work-up, 10 ml of water were added and the mixturewas extracted twice with in each case 10 ml of ethyl acetate. Thecombined organic phases were washed once with 10 ml of water and 10 mlof saturated sodium chloride solution, dried over sodium sulfate,filtered and concentrated under reduced pressure. The crude product waspurified chromatographically [Method 19]. This gave 40 mg (59% oftheory) of the target compound.

LC/MS [Method 4]: R_(t)=1.19 min; MS [ESIpos]: m/z=514 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=3.97 (dd, 1H), 4.04 (dd, 1H), 4.22 (s, 2H),4.47-4.59 (m, 1H), 4.64 (br. s, 1H), 5.25 (d, 1H), 5.32 (d, 1H),7.19-7.29 (m, 3H), 7.35-7.42 (m, 1H), 7.46-7.51 (m, 2H), 7.54-7.60 (m,2H).

Example 35-(4-Chlorophenyl)-2-{[3-(2-methylbenzyl)-1,2,4-oxadiazol-5-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

Analogously to the preparation of the compound in Example 2, 50 mg (0.13mmol) of the compound from Example 7A gave 45 mg (69% of theory) of thetitle compound.

LC/MS [Method 3]: R_(t)=1.38 min; MS [ESIpos]: m/z=494 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=2.33 (s, 3H), 3.97 (dd, 1H), 4.01-4.08 (m,3H), 4.44 (d, 1H), 4.47-4.54 (m, 1H), 5.23 (d, 1H), 5.30 (d, 1H),7.13-7.22 (m, 4H), 7.49 (d, 2H), 7.55 (d, 2H).

Example 45-(4-Chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2-({3-[3-(trifluoromethyl)benzyl]-1,2,4-oxadiazol-5-yl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

Analogously to the preparation of the compound in Example 2, 50 mg (0.13mmol) of the compound from Example 7A gave 24 mg (34% of theory) of thetitle compound.

LC/MS [Method 3]: R_(t)=1.43 min; MS [ESIpos]: m/z=548 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=3.99 (dd, 1H), 4.06 (dd, 1H), 4.14 (s, 2H),4.45-4.57 (m, 2H), 5.23-5.34 (m, 2H), 7.41-7.60 (m, 8H).

Example 55-(4-Chlorophenyl)-2-{[3-(2-methylphenyl)-1,2,4-oxadiazol-5-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

Analogously to the preparation of the compound in Example 2, 50 mg (0.13mmol) of the compound from Example 7A gave, after a reaction time of 20h, 47 mg (74% of theory) of the title compound.

LC/MS [Method 4]: R_(t)=1.22 min; MS [ESIpos]: m/z=480 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=2.60 (s, 3H), 3.98-4.06 (m, 1H), 4.06-4.12(m, 1H), 4.50 (d, 1H), 4.56 (d, 1H), 5.34-5.44 (m, 2H), 7.31 (d, 2H),7.36-7.42 (m, 1H), 7.47-7.53 (m, 2H), 7.55-7.61 (m, 2H), 7.94 (d, 1H).

Example 65-(4-Chlorophenyl)-2-{[3-(2-chlorophenyl)-1,2,4-oxadiazol-5-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

Analogously to the preparation of the compound in Example 2, 50 mg (0.13mmol) of the compound from Example 7A gave, after a reaction time of 20h, 52 mg (79% of theory) of the title compound.

LC/MS [Method 4]: R_(t)=1.17 min; MS [ESIpos]: m/z=500 and 502 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=3.95-4.15 (m, 2H), 4.51-4.62 (m, 1H),5.33-5.48 (m, 2H), 7.34-7.56 (m, 5H), 7.56-7.64 (m, 2H), 7.89 (d, 1H).

Example 75-(4-Chlorophenyl)-2-{[3-(2,6-difluorophenyl)-1,2,4-oxadiazol-5-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

Analogously to the preparation of the compound in Example 2, 50 mg (0.13mmol) of the compound from Example 7A gave, after a reaction time of 2h, 46 mg (70% of theory) of the title compound.

LC/MS [Method 4]: R_(t)=1.13 min; MS [ESIpos]: m/z=502 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=3.99 (dd, 1H), 4.08 (dd, 1H), 4.53-4.62 (m,1H), 4.66 (d, 1H), 5.36-5.49 (m, 2H), 7.01-7.10 (m, 2H), 7.44-7.54 (m,3H), 7.58-7.64 (m, 2H).

Example 85-(4-Chlorophenyl)-2-{[3-(2,3-difluorophenyl)-1,2,4-oxadiazol-5-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

Analogously to the preparation of the compound in Example 2, 50 mg (0.13mmol) of the compound from Example 7A gave, after a reaction time of 2h, 47 mg (71% of theory) of the title compound.

LC/MS [Method 4]: R_(t)=1.18 min; MS [ESIpos]: m/z=502 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=4.03 (dd, 1H), 4.07-4.13 (m, 1H), 4.38 (d,1H), 4.52-4.59 (m, 1H), 5.35-5.47 (m, 2H), 7.17-7.25 (m, 1H), 7.34 (q,1H), 7.51 (d, 2H), 7.58 (d, 2H), 7.79 (t, 1H).

Example 95-(4-Chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2-({3-[2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

Analogously to the preparation of the compound in Example 2, 50 mg (0.13mmol) of the compound from Example 7A gave 50 mg (71% of theory) of thetitle compound.

LC/MS [Method 3]: R_(t)=1.39 min; MS [ESIpos]: m/z=534 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=4.01 (dd, 1H), 4.08 (dd, 1H), 4.47-4.51 (m,1H), 4.52-4.61 (m, 1H), 5.36-5.47 (m, 2H), 7.50 (d, 2H), 7.59 (d, 2H),7.63-7.69 (m, 2H), 7.76-7.87 (m, 2H).

Example 105-(4-Chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2-({3-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

Analogously to the preparation of the compound in Example 2, 50 mg (0.13mmol) of the compound from Example 7A gave, after a reaction time of 2h, 44 mg (62% of theory) of the title compound.

LC/MS [Method 4]: R_(t)=1.25 min; MS [ESIpos]: m/z=534 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=4.05 (dd, 1H), 4.08-4.14 (m, 1H), 4.37 (d,1H), 4.52-4.58 (m, 1H), 5.35-5.45 (m, 2H), 7.50 (d, 2H), 7.56-7.61 (m,2H), 7.63 (d, 1H), 7.77 (d, 1H), 8.26 (d, 1H), 8.34 (s, 1H).

Example 115-(4-Chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2-({3-[3-(trifluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

Analogously to the preparation of the compound in Example 2, 50 mg (0.13mmol) of the compound from Example 7A gave, after a reaction time of 2h, 53 mg (73% of theory) of the title compound.

LC/MS [Method 4]: R_(t)=1.27 min; MS [ESIpos]: m/z=550 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=4.04 (dd, 1H), 4.08-4.12 (m, 1H), 4.47 (d,1H), 4.52-4.59 (m, 1H), 5.34-5.44 (m, 2H), 7.37 (d, 1H), 7.46-7.55 (m,3H), 7.56-7.61 (m, 2H), 7.93 (s, 1H), 8.01 (d, 1H).

Example 125-(4-Chlorophenyl)-2-{[3-(2,3-dichlorophenyl)-1,2,4-oxadiazol-5-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

Analogously to the preparation of the compound in Example 2, 50 mg (0.13mmol) of the compound from Example 7A gave, after a reaction time of 20h, 51 mg (72% of theory) of the title compound.

LC/MS [Method 4]: R_(t)=1.26 min; MS [ESIpos]: m/z=534 and 536 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=3.86 (dd, 1H), 3.99-4.06 (m, 1H), 4.26-4.32(m, 1H), 5.58 (s, 2H), 6.94 (d, 1H), 7.57 (t, 1H), 7.65 (d, 2H), 7.78(d, 2H), 7.86 (d, 1H), 7.91 (d, 1H).

Example 135-(4-Chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2-({3-[2-(trifluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

Analogously to the preparation of the compound in Example 2, 50 mg (0.13mmol) of the compound from Example 7A gave, after a reaction time of 20h, 37 mg (52% of theory) of the title compound.

LC/MS [Method 4]: R_(t)=1.25 min; MS [ESIpos]: m/z=550 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=3.87 (dd, 1H), 4.02 (dd, 1H), 4.25-4.34 (m,1H), 5.57 (s, 2H), 6.94 (d, 1H), 7.60-7.67 (m, 4H), 7.73-7.80 (m, 3H),8.09 (dd, 1H).

Example 145-(5-Chlorothiophen-2-yl)-4-(2-fluorobenzyl)-2-({5-[3-(trifluoromethyl)benzyl]-1,2,4-oxadiazol-3-yl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

Under argon, 81 mg (0.16 mmol) ofbenzotriazol-1-yloxy-tris(pyrrolidino)phosphonium hexafluorophosphatewere added to a solution of 29 mg (0.14 mmol) of3-(trifluoromethyl)phenylacetic acid and 27 μl (0.16 mmol) ofN,N-diisopropylethylamine in 1.3 ml of dry DMF. After 30 min ofstirring, 50 mg (0.13 mmol) of the compound from Example 25A were addedand the mixture was stirred at RT for 18 h. 2 ml of water were thenadded, and the mixture was extracted three times with in each case 5 mlof ethyl acetate. The combined organic phases were washed with in eachcase 5 ml of water and sodium chloride solution, filtered thoughExtrelut and concentrated under reduced pressure. The residue wasdissolved in 2 ml of DMF and stirred in a microwave oven at 250° C. for15 min After cooling, the solvent was removed under reduced pressure ona rotary evaporator and the crude product was purified by chromatography[Method 15]. This gave 25 mg (34% of theory) of the target compound as adark-yellow resin.

LC/MS [Method 9]: R_(t)=4.28 min; MS [ESIpos]: m/z=550 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=5.12 (s, 2H), 5.20 (s, 2H), 6.32 (d, 2H),6.90 (d, 2H), 7.04-7.19 (m, 3H), 7.22-7.34 (m, 1H), 7.43-7.55 (m, 2H),7.55-7.62 (m, 2H).

Example 155-(5-Chlorothiophen-2-yl)-4-(2-fluorobenzyl)-2-({5-[2-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

Analogously to the preparation of the compound in Example 14, 50 mg(0.13 mmol) of the compound from Example 25A gave 35 mg (49% of theory)of the title compound.

MS [ESIpos]: m/z=536 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=5.16 (s, 2H), 5.35 (s, 2H), 6.33 (d, 2H),6.92 (d, 2H), 7.04-7.13 (m, 2H), 7.13-7.20 (m, 1H), 7.23-7.33 (m, 1H),7.68-7.78 (m, 2H), 7.83-7.92 (m, 1H), 7.96-8.05 (m, 1H).

Example 165-(5-Chlorothiophen-2-yl)-4-(2-fluorobenzyl)-2-({5-[2-(trifluoromethyl)benzyl]-1,2,4-oxadiazol-3-yl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

Analogously to the preparation of the compound in Example 14, 50 mg(0.13 mmol) of the compound from Example 25A gave 15 mg (20% of theory)of the title compound.

MS [CIpos]: m/z=550 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=4.93 (s, 2H), 5.14 (s, 2H), 5.20 (s, 2H),6.82 (d, 2H), 6.90 (d, 2H), 7.04-7.18 (m, 3H), 7.25-7.35 (m, 1H),7.35-7.50 (m, 2H), 7.50-7.59 (m, 1H), 7.66-7.75 (m, 1H).

Example 175-(4-Chlorophenyl)-2-{[5-(2-chlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

85 mg (0.28 mmol) of the compound from Example 5A were dissolved in 5 mlof acetonitrile, and 180 mg (0.55 mmol) of cesium carbonate and 66 mg(0.29 mmol) of 2-(chloromethyl)-5-(2-chlorophenyl)-1,3,4-oxadiazole wereadded. The mixture was stirred at 80° C. for 1 h. For work-up, themixture was cooled to RT, and 10 ml of water were added. The mixture wasextracted twice with in each case 15 ml of ethyl acetate. The combinedorganic phases were dried over sodium sulfate, filtered and concentratedunder reduced pressure. The crude product was purifiedchromatographically [Method 19]. This gave 66 mg (48% of theory) of thetarget compound.

LC/MS [Method 4]: R_(t)=1.12 min; MS [ESIpos]: m/z=500 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.85 (dd, 1H), 4.01 (dd, 1H), 4.25-4.31 (m,1H), 5.41-5.51 (m, 2H), 6.90 (d, 1H), 7.55-7.60 (m, 1H), 7.61-7.69 (m,3H), 7.70-7.78 (m, 3H), 7.94 (dd, 1H).

Example 185-(4-Chlorophenyl)-2-{[5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

30 mg (0.10 mmol) of the compound from Example 5A were dissolved in 3 mlof acetonitrile, and 48 mg (0.15 mmol) of cesium carbonate and 28 mg(0.10 mmol) of the compound from Example 86A were added. The mixture wasstirred at 70° C. for 8 h. For work-up, the mixture was cooled to RT,diluted with 5 ml of methanol and filtered. The filtrate wasconcentrated under reduced pressure and the crude product was thenpurified chromatographically [Method 19]. This gave 11 mg (22% oftheory) of the target compound.

LC/MS [Method 6]: R_(t)=2.48 min; MS [ESIpos]: m/z=516 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.85 (dd, 1H), 4.01 (dd, 1H), 4.24-4.35 (m,1H), 5.56-5.65 (m, 2H), 6.92 (s, 1H), 7.53-7.59 (m, 1H), 7.59-7.67 (m,3H), 7.72 (dd, 1H), 7.77 (d, 2H), 8.14 (dd, 1H).

Example 195-(4-Chlorophenyl)-2-{[5-(2,3-dichlorophenyl)-1,3,4-thiadiazol-2-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

Analogously to the preparation of Example 18, 36 mg (0.12 mmol) of thecompound from Example 5A were reacted with 38 mg (0.12 mmol) of thecompound from Example 87A. This gave 33 mg (48% of theory) of the targetcompound.

LC/MS [Method 4]: R_(t)=1.25 min; MS [ESIpos]: m/z=550 and 552 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.85 (dd, 1H), 4.01 (dd, 1H), 4.25-4.35 (m,1H), 5.56-5.66 (m, 2H), 6.94 (br. s, 1H), 7.57 (t, 1H), 7.64 (d, 2H),7.78 (d, 2H), 7.90 (dd, 1H), 8.05 (dd, 1H).

Example 205-(4-Chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2-({5-[2-(trifluoromethyl)phenyl]-1,3,4-thiadiazol-2-yl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

Analogously to the preparation of Example 18, 33 mg (0.11 mmol) of thecompound from Example 5A were reacted with 35 mg (0.11 mmol) of thecompound from Example 85A. This gave 16 mg (27% of theory) of the targetcompound.

LC/MS [Method 3]: R_(t)=1.33 min; MS [ESIpos]: m/z=550 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.86 (dd, 1H), 4.02 (dd, 1H), 4.25-4.35 (m,1H), 5.56-5.65 (m, 2H), 6.92 (br. s, 1H), 7.62-7.67 (m, 2H), 7.75-7.88(m, 5H), 7.97-8.01 (m, 1H).

Example 215-(4-Chlorophenyl)-4-cyclopropyl-2-({5-[3-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

100 mg (0.33 mmol) of the compound from Example 21A were dissolved in1.6 ml of DMF, 109 mg (0.49 mmol) of 3-trifluoromethylbenzamidinehydrochloride were added and the mixture was stirred in a microwave ovenat 150° C. for 45 min After cooling, the reaction was concentrated underreduced pressure on a rotary evaporator and the residue that remainedwas purified chromatographically [Method 19]. This gave 70 mg (47% oftheory) of the target compound as a colorless solid.

LC/MS [Method 7]: R_(t)=2.33 min; MS [ESIpos]: m/z=461 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=0.74-0.84 (m, 2H), 0.99-1.10 (m, 2H),2.96-3.06 (m, 1H), 5.28 (s, 2H), 7.45 (d, 2H), 7.53 (t, 1H), 7.64 (d,1H), 7.68 (d, 2H), 8.25 (d, 1H), 8.36 (s, 1H).

Example 225-(4-Chlorophenyl)-4-cyclopropyl-2-({5-[2-(trifluoromethyl)benzyl]-4H-1,2,4-triazol-3-yl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

Analogously to the preparation of the compound in Example 21, 100 mg(0.33 mmol) of the compound from Example 21A gave 54 mg (35% of theory)of the title compound.

MS [ESIpos]: m/z=475 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=0.70-0.80 (m, 2H), 0.96-1.06 (m, 2H),2.92-3.03 (m, 1H), 4.30 (s, 2H), 5.15 (s, 2H), 7.30-7.40 (m, 2H),7.40-7.51 (m, 3H), 7.61-7.71 (m, 3H), 10.80 (br. s, 1H).

Example 235-(4-Chlorophenyl)-4-cyclopropyl-2-({5-[3-(trifluoromethyl)benzyl]-4H-1,2,4-triazol-3-yl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

Analogously to the preparation of the compound in Example 21, 75 mg(0.24 mmol) of the compound from Example 21A gave 55 mg (48% of theory)of the title compound.

LC/MS [Method 5]: R_(t)=2.42 min; MS [ESIpos]: m/z=475 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=0.70-0.79 (m, 2H), 0.96-1.06 (m, 2H),2.93-3.03 (m, 1H), 4.14 (s, 2H), 5.15 (s, 2H), 7.38-7.51 (m, 5H), 7.56(s, 1H), 7.62-7.70 (m, 2H).

Example 245-(4-Chlorophenyl)-4-cyclopropyl-2-{[5-(2,6-dichlorobenzyl)-4H-1,2,4-triazol-3-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one

58 mg (0.24 mmol) of 2-(2,6-dichlorophenyl)ethaneimidamide hydrochloridewere initially charged in 1 ml of dry methanol, 66 μl (0.24 mmol) of a25% strength methanolic sodium methoxide solution were added and themixture was stirred at RT for 1 h. 50 mg (0.16 mmol) of the compoundfrom Example 21A, dissolved in 0.6 ml of methanol, were then added. Thereaction was stirred at room temperature overnight. The precipitatedcolorless solid was filtered off with suction, washed with a littlemethanol and dried under high vacuum. The solid was then suspended inxylene and stirred under reflux for 4 h. After cooling, the mixture wasconcentrated under reduced pressure and the residue was purified bychromatography [Method 19]. This gave 30 mg (39% of theory) of thetarget compound as a colorless solid.

LC/MS [Method 5]: R_(t)=2.38 min; MS [ESIpos]: m/z=476 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=0.70-0.80 (m, 2H), 0.96-1.06 (m, 2H),2.93-3.04 (m, 1H), 4.46 (s, 2H), 5.13 (s, 2H), 7.19 (t, 1H), 7.35 (d,2H), 7.44 (d, 2H), 7.67 (d, 2H), 11.00 (br. s, 1H).

Example 255-(5-Chlorothiophen-2-yl)-4-(2-fluorobenzyl)-2-({5-[3-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

100 mg (0.26 mmol) of the compound from Example 22A were dissolved in1.0 ml of DMF, 88 mg (0.39 mmol) of3-(trifluoromethyl)benzenecarboximidamide hydrochloride were added andthe mixture was stirred in a microwave oven at 220° C. for 30 min Aftercooling, the reaction was concentrated under reduced pressure on arotary evaporator, and the residue was purified chromatographically[Method 19]. This gave 71 mg (51% of theory) of the target compound as acolorless resin.

MS [ESIpos]: m/z=535 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=5.14 (s, 2H), 5.34 (s, 2H), 6.85 (s, 1H),6.95 (s, 1H), 7.04-7.16 (m, 3H), 7.28-7.37 (m, 1H), 7.50-7.60 (m, 1H),7.61-7.70 (m, 1H), 8.20-8.30 (m, 1H), 8.35 (s, 1H), 12.00 (br. s, 1H).

Example 265-(5-Chlorothiophen-2-yl)-4-(2-fluorobenzyl)-2-({5-[2-(trifluoromethyl)benzyl]-4H-1,2,4-triazol-3-yl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

Analogously to the preparation of the compound in Example 25, 75 mg(0.20 mmol) of the compound from Example 22A gave 19 mg (18% of theory)of the title compound.

LC/MS [Method 5]: R_(t)=2.62 min; MS [ESIpos]: m/z=549 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=4.32 (s, 2H), 5.11 (s, 2H), 5.21 (s, 2H),6.82 (d, 1H), 6.90 (d, 1H), 7.03-7.16 (m, 3H), 7.25-7.32 (m, 1H),7.32-7.44 (m, 2H), 7.45-7.52 (m, 1H), 7.68 (d, 1H), 10.70 (br. s, 1H).

Example 275-(5-Chlorothiophen-2-yl)-4-(2-fluorobenzyl)-2-({5-[3-(trifluoromethyl)benzyl]-4H-1,2,4-triazol-3-yl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

Analogously to the preparation of the compound in Example 25, 75 mg(0.20 mmol) of the compound from Example 22A gave 29 mg (27% of theory)of the title compound.

MS [ESIpos]: m/z=549 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=4.15 (s, 2H), 5.11 (s, 2H), 5.22 (s, 2H),6.84 (d, 1H), 6.91 (d, 1H), 7.03-7.15 (m, 3H), 7.25-7.34 (m, 1H), 7.44(d, 1H), 7.48-7.53 (m, 2H), 7.58 (s, 1H), 11.10 (br. s, 1H).

Example 28 Methyl3-{[3-(4-chlorophenyl)-5-oxo-1-({5-[2-(trifluoromethyl)benzyl]-4H-1,2,4-triazol-3-yl}-methyl)-1,5-dihydro-4H-1,2,4-triazol-4-yl]methyl}benzenecarboxylate

77 mg (0.27 mmol) of 2-[2-(trifluoromethyl)phenyl]ethaneimidamidehydrobromide were dissolved in 1 ml of dry methanol, 74 μl (0.27 mmol)of a 25% strength methanolic sodium methoxide solution were added andthe mixture was stirred for 30 min 75 mg (0.18 mmol) of the compoundfrom Example 16A were then added, and the mixture was stirred initiallyat RT for 16 h and then under reflux for 5 h. The mixture was thendirectly purified chromatographically [Method 19]. This gave 67 mg (64%of theory) of the target compound as a colorless foam.

LC/MS [Method 5]: R_(t)=2.59 min; MS [ESIpos]: m/z=583 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=3.88 (s, 3H), 4.31 (s, 2H), 5.00 (s, 2H),5.25 (s, 2H), 7.29-7.44 (m, 8H), 7.49 (d, 1H), 7.58 (d, 1H), 7.90 (s,1H), 7.95 (d, 1H).

Example 29 Methyl3-{[3-(4-chlorophenyl)-1-{[5-(2,6-dichlorobenzyl)-4H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]methyl}benzenecarboxylate

Analogously to the preparation of the compound in Example 28, 80 mg(0.19 mmol) of the compound from Example 16A gave 67 mg (60% of theory)of the title compound.

MS [ESIpos]: m/z=583 and 585 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=3.90 (s, 3H), 4.49 (s, 2H), 5.00 (s, 2H),5.24 (s, 2H), 7.19 (t, 1H), 7.28-7.44 (m, 8H), 7.88-8.00 (m, 2H), 11.20(br. s, 1H).

Example 305-(4-Chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2-({5-[2-(trifluoromethyl)benzyl]-4H-1,2,4-triazol-3-yl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

370 mg (0.97 mmol) of the compound from Example 18A were dissolved in 5ml of DMF, 349 mg (1.46 mmol) of2-[2-(trifluoromethyl)phenyl]ethaneimidamide hydrochloride were addedand the mixture was stirred in a microwave oven at 200° C. for 90 minAfter cooling, the reaction was diluted with 5 ml of methanol anddirectly purified chromatographically [Method 19]. This gave 170 mg (32%of theory) of the target compound.

LC/MS [Method 3]: R_(t)=1.24 min; MS [ESIpos]: m/z=547 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=3.87-4.00 (m, 2H), 4.21 (s, 2H), 4.56-4.62(m, 1H), 5.03-5.21 (m, 2H), 5.70 (br. s, 1H), 7.31 (d, 1H), 7.38 (t,1H), 7.44 (d, 2H), 7.49 (t, 1H), 7.59 (s, 2H), 7.67 (d, 1H), 11.48 (br.s, 1H).

Example 313-{[3-(4-Chlorophenyl)-5-oxo-1-({5-[2-(trifluoromethyl)benzyl]-4H-1,2,4-triazol-3-yl}methyl)-1,5-dihydro-4H-1,2,4-triazol-4-yl]methyl}benzenecarboxylicacid

62 mg (0.11 mmol) of the compound from Example 28 were suspended in 1 mlof ethanol, and 213 μl (0.21 mmol) of 1 M aqueous sodium hydroxidesolution were added. The mixture was stirred at 50° C. for 4 h. Aftercooling to RT, the reaction was neutralized with 215 μl of 1 Mhydrochloric acid and concentrated under reduced pressure, and theresidue was purified by chromatography [Method 19]. This gave 37 mg (61%of theory) of the target compound as a colorless foam.

MS [ESIpos]: m/z=569 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=4.04-4.35 (m, 2H), 4.90-5.25 (m, 4H),7.25-7.38 (m, 1H), 7.38-7.54 (m, 7H), 7.54-7.65 (m, 1H), 7.65-7.78 (m,2H), 7.80 (d, 1H), 13.02 (br. s, 1H), 13.65-13.93 (br. s, 1H).

Example 323-{[3-(4-Chlorophenyl)-1-{[5-(2,6-dichlorobenzyl)-4H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]methyl}benzenecarboxylicacid

Analogously to the preparation of the compound in Example 31, 60 mg(0.10 mmol) of the compound from Example 29 gave 40 mg (68% of theory)of the title compound.

MS [ESIpos]: m/z=569 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=4.16-4.44 (m, 2H), 4.85-5.25 (m, 4H),7.24-7.40 (m, 2H), 7.43 (t, 1H), 7.45-7.58 (m, 6H), 7.70 (s, 1H), 7.82(d, 1H), 13.03 (br. s, 1H), 13.70 (br. s, 1H).

Example 335-(4-Chlorophenyl)-4-cyclopropyl-2-[(5-{2-[3-(trifluoromethyl)phenyl]propan-2-yl}-4H-1,2,4-triazol-3-yl)methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

42 mg (0.14 mmol) of the compound from Example 21A were dissolved in 1.2ml of DMF, 40 mg (0.15 mmol) of 2-methyl2-[3-(trifluoromethyl)phenyl]propaneimidamide hydrochloride and 9 mg(0.16 mmol) of sodium methoxide were added and the mixture was stirredin a microwave reactor at 180° C. for 2 h. After cooling to RT, themixture was purified directly by preparative HPLC [Method 19]. This gave2 mg (3% of theory) of the target compound as a colorless foam.

LC/MS [Method 1]: R_(t)=2.06 min; MS [ESIpos]: m/z=503 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=0.75-0.79 (m, 2H), 1.00-1.05 (m, 2H), 1.79(s, 6H), 2.96-3.02 (m, 1H), 5.16 (s, 2H), 7.38-7.43 (q, 1H), 7.45 (d,2H), 7.46-7.49 (m, 2H), 7.59 (s, 1H), 7.67 (d, 2H).

Example 345-(4-Chlorophenyl)-4-cyclopropyl-2-({5-[1-(2-fluorophenyl)-1-methylethyl]-4H-1,2,4-triazol-3-yl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

60 mg (0.20 mmol) of the compound from Example 21A were dissolved in 1ml of DMF, and 63 mg (0.29 mmol) of2-(2-fluorophenyl)-2-methylpropaneimidamide hydrochloride and 17 mg(0.31 mmol) of sodium methoxide were added. The suspension was stirredat 150° C. for 8 h. The reaction was then brought to completion by 45min of stirring in a microwave reactor at 200° C. The suspension wasdiluted with about 1 ml of methanol and filtered, and the filtrate waspurified by preparative HPLC [Method 19]. This gave 13 mg (15% oftheory) of the title compound.

LC/MS [Method 5]: R_(t)=2.30 min; MS [ESIpos]: m/z=453 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=0.75 (m, 2H), 0.95 (m, 2H), 1.88 (s, 6H),2.99 (m, 1H), 5.32 (s, 2H), 6.93-7.00 (m, 1H), 7.14-7.21 (m, 1H),7.38-7.49 (m, 4H), 7.62-7.72 (m, 2H).

Example 355-(4-Chlorophenyl)-4-cyclopropyl-2-[(5-{2-[3-(trifluoromethyl)phenyl]ethyl}-4H-1,2,4-triazol-3-yl)methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

50 mg (0.16 mmol) of the compound from Example 21A were taken up in 1 mlof DMF, 62 mg (0.24 mmol) of3-[3-(trifluoromethyl)phenyl]propaneimidamide hydrochloride were addedand the mixture was stirred in a microwave oven at 180° C. for 1 h.After cooling, the reaction mixture was diluted with methanol and thesolution was directly separated by preparative HPLC [Method 19]. Thisgave 11 mg (14% of theory) of the title compound.

LC/MS [Method 1]: R_(t)=1.96 min; MS [ESIpos]: m/z=489 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=0.71-0.81 (m, 2H), 0.98-1.06 (m, 2H), 2.99(m, 1H), 3.03-3.09 (m, 2H), 3.10-3.16 (m, 2H), 5.16 (s, 2H), 7.37 (d,2H), 7.41-7.48 (m, 4H), 7.68 (d, 2H).

Example 365-(4-Chlorophenyl)-4-cyclopropyl-2-{[5-(2-ethoxybenzyl)-4H-1,2,4-triazol-3-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one

50 mg (0.16 mmol) of the compound from Example 21A were taken up in 1 mlof DMF, 52 mg (0.24 mmol) of 2-(2-ethoxyphenyl)ethaneimidamidehydrochloride were added and the mixture was stirred in a microwave ovenat 200° C. for 1 h. After cooling, the reaction was diluted with about 1ml of methanol and the solution was directly separated by preparativeHPLC [Method 19]. This gave 21 mg (28% of theory) of the title compound.

LC/MS [Method 3]: R_(t)=1.14 min; MS [ESIpos]: m/z=451 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=0.75-0.79 (m, 2H), 0.97-1.02 (m, 2H), 1.44(t, 3H), 2.97 (m, 1H), 4.09-4.14 (m, 4H), 5.10 (s, 2H), 6.91 (t, 2H),7.25 (t, 2H), 7.41 (2d, 2H), 7.67 (d, 2H).

Example 375-(4-Chlorophenyl)-4-cyclopropyl-2-{[5-(3-fluorobenzyl)-4H-1,2,4-triazol-3-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one

Analogously to the preparation of the compound in Example 36, 50 mg(0.16 mmol) of the compound from Example 21A gave 11 mg (16% of theory)of the title compound.

LC/MS [Method 5]: R_(t)=2.16 min; MS [ESIpos]: m/z=425 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=0.75-0.79 (m, 2H), 0.99-1.05 (m, 2H), 2.98(m, 1H), 4.10 (s, 2H), 5.15 (s, 2H), 6.93 (m, 1H), 7.00 (d, 1H), 7.07(d, 1H), 7.23-7.30 (m, 1H), 7.44 (d, 2H), 7.67 (d, 2H).

Example 385-(4-Chlorophenyl)-4-cyclopropyl-2-{[5-(2-methoxybenzyl)-4H-1,2,4-triazol-3-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one

Analogously to the preparation of the compound in Example 36, 50 mg(0.16 mmol) of the compound from Example 21A gave 11 mg (16% of theory)of the title compound.

LC/MS [Method 3]: R_(t)=1.09 min; MS [ESIpos]: m/z=437 (M+H)⁺.

Example 395-(4-Chlorophenyl)-4-cyclopropyl-2-{[5-(3-methylbenzyl)-4H-1,2,4-triazol-3-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one

Analogously to the preparation of the compound in Example 36, 50 mg(0.16 mmol) of the compound from Example 21A gave 11 mg (16% of theory)of the title compound.

LC/MS [Method 3]: R_(t)=1.13 min; MS [ESIpos]: m/z=421 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=0.73-0.79 (m, 2H), 0.97-1.04 (m, 2H), 2.31(s, 3H), 2.93-3.01 (m, 1H), 4.07 (s, 2H), 5.13 (s, 2H), 7.04-7.11 (m,3H), 7.18-7.23 (m, 1H), 7.43 (d, 2H), 7.67 (d, 2H).

Example 402-{[5-(2-Chlorobenzyl)-4H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-cyclopropyl-2,4-dihydro-3H-1,2,4-triazol-3-one

Analogously to the preparation of the compound in Example 36, 50 mg(0.16 mmol) of the compound from Example 21A gave 22 mg (31% of theory)of the title compound.

LC/MS [Method 3]: R_(t)=1.13 min; MS [ESIpos]: m/z=441 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=0.74-0.79 (m, 2H), 0.99-1.04 (m, 2H), 2.98(m, 1H), 4.25 (s, 2H), 5.14 (s, 2H), 7.21-7.23 (m, 2H), 7.30-7.32 (m,1H), 7.38-7.40 (m, 1H), 7.44 (d, 2H), 7.67 (d, 2H).

Example 415-(4-Chlorophenyl)-4-cyclopropyl-2-{[5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one

Analogously to the preparation of the compound in Example 36, 50 mg(0.16 mmol) of the compound from Example 21A gave 11 mg (16% of theory)of the title compound.

LC/MS [Method 5]: R_(t)=2.07 min; MS [ESIpos]: m/z=425 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=0.74-0.79 (m, 2H), 0.98-1.05 (m, 2H), 2.98(m, 1H), 4.14 (s, 2H), 5.14 (s, 2H), 7.03-7.12 (m, 2H), 7.21-7.31 (m,2H), 7.44 (d, 2H), 7.67 (d, 2H).

Example 425-(4-Chlorophenyl)-2-{[5-(2,6-dichlorobenzyl)-4H-1,2,4-triazol-3-yl]methyl}-4-(4-methoxybenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

Analogously to the preparation of the compound in Example 36, 70 mg(0.18 mmol) of the compound from Example 17A gave 36 mg (36% of theory)of the title compound.

LC/MS [Method 3]: R_(t)=1.30 min; MS [ESIpos]: m/z=557 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=3.78 (s, 3H), 4.47 (s, 2H), 4.86 (s, 2H),5.22 (s, 2H), 6.82 (d, 2H), 7.06 (d, 2H), 7.18 (t, 1H), 7.33-7.39 (m,6H).

Example 435-(4-Chlorophenyl)-2-{[5-(2,6-dichlorobenzyl)-4H-1,2,4-triazol-3-yl]methyl}-4-[(2R)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

Analogously to the preparation of the compound in Example 36, 70 mg(0.18 mmol) of the compound from Example 20A gave 21 mg (21% of theory)of the title compound.

LC/MS [Method 3]: R_(t)=1.23 min; MS [ESIpos]: m/z=548 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=3.86-3.99 (m, 2H), 4.36-4.45 (m, 2H),4.56-4.66 (m, 1H), 5.07 (d, 1H), 5.18 (d, 1H), 7.20 (t, 1H), 7.35 (d,2H), 7.44 (d, 2H), 7.58 (d, 2H).

Example 445-(4-Chlorophenyl)-4-[(2R)-3,3,3-trifluoro-2-hydroxypropyl]-2-({5-[3-(trifluoromethyl)benzyl]-4H-1,2,4-triazol-3-yl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

Analogously to the preparation of the compound in Example 36, 70 mg(0.18 mmol) of the compound from Example 20A gave 21 mg (21% of theory)of the title compound.

LC/MS [Method 5]: R_(t)=2.43 min; MS [ESIpos]: m/z=547 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=3.86-4.00 (m, 2H), 4.05 (s, 2H), 4.56-4.66(m, 1H), 5.08 (d, 1H), 5.21 (d, 1H), 7.38-7.47 (m, 4H), 7.50-7.55 (m,2H), 7.61 (d, 2H).

Example 455-(4-Chlorophenyl)-4-[(2R)-3,3,3-trifluoro-2-hydroxypropyl]-2-[(5-{2-[3-(trifluoromethyl)phenyl]-ethyl}-4H-1,2,4-triazol-3-yl)methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

Analogously to the preparation of the compound in Example 36, 70 mg(0.18 mmol) of the compound from Example 20A gave 18 mg (17% of theory)of the title compound.

LC/MS [Method 5]: R_(t)=2.49 min; MS [ESIpos]: m/z=561 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=2.91-2.99 (m, 2H), 3.02-3.10 (m, 2H),3.87-4.01 (m, 2H), 4.59-4.69 (m, 1H), 5.09 (d, 1H), 5.25 (d, 1H), 7.32(d, 1H), 7.38 (m, 1H), 7.41-7.49 (m, 2H), 7.44 (d, 2H), 7.63 (d, 2H).

Example 462-{[5-(2-Chlorobenzyl)-4H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2R)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

Analogously to the preparation of the compound in Example 36, 70 mg(0.18 mmol) of the compound from Example 20A gave 17 mg (18% of theory)of the title compound.

LC/MS [Method 5]: R_(t)=2.30 min; MS [ESIpos]: m/z=513 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=3.83-3.97 (m, 2H), 4.04-4.16 (m, 2H),4.59-4.70 (m, 1H), 5.03 (d, 1H), 5.14 (d, 1H), 7.19-7.25 (m, 3H),7.36-7.40 (m, 1H), 7.42 (d, 2H), 7.59 (d, 2H).

Example 475-(4-Chlorophenyl)-2-{[5-(2-methoxybenzyl)-4H-1,2,4-triazol-3-yl]methyl}-4-[(2R)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

Analogously to the preparation of the compound in Example 36, 70 mg(0.18 mmol) of the compound from Example 20A gave 16 mg (17% of theory)of the title compound.

LC/MS [Method 5]: R_(t)=2.25 min; MS [ESIpos]: m/z=509 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=3.86 (s, 3H), 3.83-3.99 (m, 2H), 4.01 (s,2H), 4.63-4.71 (m, 1H), 5.01 (d, 1H), 5.19 (d, 1H), 6.02 (d, 1H),6.88-6.95 (m, 2H), 7.13-7.19 (m, 1H), 7.25-7.29 (m, 1H), 7.43 (d, 2H),7.61 (d, 2H), 11.03-11.15 (br. s, 1H).

Example 485-(4-Chlorophenyl)-2-{[5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-yl]methyl}-4-[(2R)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

Analogously to the preparation of the compound in Example 36, 100 mg(0.26 mmol) of the compound from Example 20A gave 34 mg (26% of theory)of the title compound.

LC/MS [Method 5]: R_(t)=2.24 min; MS [ESIpos]: m/z=497 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=3.83-3.98 (m, 2H), 3.97-4.03 (m, 2H),4.59-4.71 (m, 1H), 5.02 (d, 1H), 5.15 (d, 1H), 6.00 (br. s, 1H),7.02-7.12 (m, 2H), 7.15-7.21 (m, 1H), 7.22-7.30 (m, 1H), 7.42 (d, 2H),7.60 (d, 2H), 11.87 (br. s, 1H).

Example 492-{[5-(2-Chlorobenzyl)-4H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

Analogously to the preparation of the compound in Example 36, 138 mg(0.36 mmol) of the compound from Example 19A gave 35 mg (19% of theory)of the title compound.

LC/MS [Method 3]: R_(t)=1.20 min; MS [ESIpos]: m/z=513 and 515 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=3.89 (dd, 1H), 3.96 (dd, 1H), 4.07-4.18 (m,2H), 4.58-4.69 (m, 1H), 5.05+5.16 (2d, 2H), 5.90 (br. s, 1H), 7.20-7.25(m, 3H), 7.36-7.41 (m, 1H), 7.43 (d, 2H), 7.57-7.61 (m, 2H), 11.65 (br.s, 1H).

Example 505-(4-Chlorophenyl)-2-{[5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

Analogously to the preparation of the compound in Example 36, 124 mg(0.33 mmol) of the compound from Example 19A gave 37 mg (23% of theory)of the title compound.

LC/MS [Method 3]: R_(t)=1.16 min; MS [ESIpos]: m/z=497 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=3.89 (dd, 1H), 3.97 (dd, 1H), 3.98-4.08 (m,2H), 4.61-4.70 (m, 1H), 5.04+5.16 (2d, 2H), 5.86 (br. s, 1H), 7.03-7.31(m, 4H), 7.43 (d, 2H), 7.59 (d, 2H), 11.65 (br. s, 1H).

Example 515-(4-Chlorophenyl)-2-{[5-(2,6-dichlorobenzyl)-4H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

Analogously to the preparation of the compound in Example 36, 106 mg(0.28 mmol) of the compound from Example 19A gave 49 mg (32% of theory)of the title compound.

LC/MS [Method 4]: R_(t)=1.08 min; MS [ESIpos]: m/z=547 and 549 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=3.88 (dd, 1H), 3.96 (dd, 1H), 4.34-4.46 (m,2H), 4.57-4.67 (m, 1H), 5.03-5.22 (m, 2H), 7.16-7.23 (m, 1H), 7.35 (d,2H), 7.44 (d, 2H), 7.60 (d, 2H).

Example 525-(4-Chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2-({5-[3-(trifluoromethoxy)benzyl]-4H-1,2,4-triazol-3-yl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

Analogously to the preparation of the compound in Example 36, 120 mg(0.32 mmol) of the compound from Example 19A gave 83 mg (47% of theory)of the title compound.

LC/MS [Method 2]: R_(t)=2.39 min; MS [ESIpos]: m/z=563 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=3.86-3.96 (m, 2H), 3.95-4.05 (m, 2H),4.57-4.67 (m, 1H), 5.04-5.24 (m, 2H), 7.09-7.17 (m, 3H), 7.30-7.36 (m,1H), 7.45 (d, 2H), 7.60 (d, 2H).

Example 535-(4-Chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2-({5-[2-(trifluoromethyl)benzyl]-4H-1,2,4-triazol-3-yl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

1190 mg (3.13 mmol) of the compound from Example 19A were reactedanalogously to the preparation of the compound in Example 36. Forwork-up, the reaction mixture was diluted with 25 ml of water andextracted twice with in each case 25 ml of ethyl acetate. The combinedorganic phases were dried over sodium sulfate, filtered and concentratedunder reduced pressure. The crude product was purifiedchromatographically [Method 19]. This gave 932 mg (54% of theory) of thetitle compound.

LC/MS [Method 4]: R_(t)=1.08 min; MS [ESIpos]: m/z=547 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=3.83-3.96 (m, 2H), 4.11-4.22 (m, 2H),4.56-4.68 (m, 1H), 5.00-5.18 (m, 2H), 5.88 (br. s, 1H), 7.25-7.29 (m,1H), 7.33-7.52 (m, 4H), 7.58 (d, 2H), 7.67 (d, 1H), 11.89 (br. s, 1H).

Example 545-(4-Chlorophenyl)-2-{[5-(2-chlorophenyl)-4H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

1200 mg (3.16 mmol) of the compound from 19A were taken up in 15 ml ofDMF, 906 mg (4.74 mmol) of 2-chlorobenzenecarboximidamide hydrochloridewere added and the mixture was stirred in a microwave oven at 220° C.for 1 h. After cooling, 20 ml of 1 N hydrochloric acid were added andthe mixture was extracted twice with in each case 25 ml of ethylacetate. The combined organic phases were dried over sodium sulfate,filtered and concentrated under reduced pressure. Further purificationwas carried out by chromatography on silica gel (mobile phase:cyclohexane/ethyl acetate 2:1, then 1:1). This gave 395 mg (80% oftheory) of the title compound of a purity of 80%.

LC/MS [Method 4]: R_(t)=1.02 min; MS [ESIpos]: m/z=499 and 501 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.85 (dd, 1H), 4.00 (dd, 1H), 4.25-4.37 (m,1H), 5.00-5.30 (m, 2H), 6.92 (d, 1H), 7.40-7.67 (m, 5H), 7.71-7.81 (m,3H), 14.27 (br. s, 1H).

Example 55Methyl(3-{[3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]methyl}-5-[2-(trifluoromethyl)benzyl]-1H-1,2,4-triazol-1-yl)acetateandmethyl(5-{[3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]methyl}-3-[2-(trifluoromethyl)benzyl]-1H-1,2,4-triazol-1-yl)acetate(mixture of regioisomers)

350 mg (0.57 mmol) of the compound from Example 30 were dissolved in 9ml of DMF, and 27 mg (0.68 mmol) of sodium hydride (60% in paraffin)were added. The mixture was stirred at RT for 10 min 68 mg (0.63 mmol)of methyl chloroacetate were then added, and the mixture was stirred at40° C. for 30 min. For work-up, 10 ml of water were added, and themixture was extracted twice with in each case 15 ml of ethyl acetate.The combined organic phases were dried over sodium sulfate, filtered andconcentrated under reduced pressure. The crude product was purifiedchromatographically [Method 19]; it was not possible to separate theregioisomers during the purification. This gave 310 mg (88% of theory)of a mixture of the regioisomeric title compounds which was reactedfurther as such (see Examples 58 and 59).

LC/MS [Method 5]: R_(t)=2.52 min; MS [ESIpos]: m/z=619 (M+H)⁺ andR_(t)=2.60 min; MS [ESIpos]: m/z=619 (M+H)⁺.

Example 56 and Example 57Methyl[5-(2-chlorophenyl)-3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1H-1,2,4-triazol-1-yl]acetate(regioisomer 1) andmethyl[3-(2-chlorophenyl)-5-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1H-1,2,4-triazol-1-yl]acetate(regioisomer 2)

395 mg (0.79 mmol) of the compound from Example 54 were dissolved in 10ml of DMF, and 38 mg (0.95 mmol) of sodium hydride (60% in paraffin)were added. The mixture was stirred at RT for 10 min 94 mg (0.87 mmol)of methyl chloroacetate were then added, and the mixture was stirred at40° C. for 30 min After cooling to RT, the reaction mixture wasdirectly, without any further work-up, purified chromatographically[Method 19] with complete separation of the regioisomers. This gave 71mg (16% of theory) of regioisomer 1 (Example 56) and 210 mg (46% oftheory) of regioisomer 2 (Example 57).

Example 56

LC/MS [Method 4]: R_(t)=1.09 min; MS [ESIpos]: m/z=571 and 573 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=3.69 (s, 3H), 3.94 (dd, 1H), 4.05 (dd, 1H),4.55-4.64 (m, 1H), 4.80 (s, 2H), 5.14-5.33 (m, 2H), 5.36 (d, 1H),7.34-7.40 (m, 1H), 7.42-7.52 (m, 5H), 7.54-7.60 (m, 2H).

Example 57

LC/MS [Method 4]: R_(t)=1.15 min; MS [ESIpos]: m/z=571 and 573 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=3.74 (s, 3H), 3.92 (dd, 1H), 3.99 (dd, 1H),4.55-4.65 (m, 1H), 4.89 (d, 1H), 5.16-5.39 (m, 4H), 7.28-7.34 (m, 2H),7.42-7.50 (m, 3H), 7.59-7.64 (m, 2H), 7.85-7.91 (m, 1H).

Example 58 and Example 59(3-{[3-(4-Chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]methyl}-5-[2-(trifluoromethyl)benzyl]-1H-1,2,4-triazol-1-yl)aceticacid (regioisomer 1) and(5-{[3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]methyl}-3-[2-(trifluoromethyl)benzyl]-1H-1,2,4-triazol-1-yl)aceticacid (regioisomer 2)

310 mg (0.50 mmol) of the compound from Example 55 (as a mixture ofregioisomers) were dissolved in 5 ml of methanol, and 0.85 ml (0.85mmol) of a 1 N aqueous lithium hydroxide solution was added. The mixturewas stirred at RT for 45 min. The mixture was then freed from thesolvent under reduced pressure, taken up in 10 ml of water andneutralized with 0.85 ml (0.85 mmol) of 1 N hydrochloric acid. Themixture was extracted twice with in each case 15 ml of ethyl acetate.The combined organic phases were dried over sodium sulfate, filtered andconcentrated under reduced pressure. The crude product was purifiedchromatographically with separation of the regioisomers [Method 16].This gave 81 mg (27% of theory) of regioisomer 1 (Example 58) and 83 mg(27% of theory) of regioisomer 2 (Example 59).

Example 58

LC/MS [Method 2]: R_(t)=2.27 min; MS [ESIpos]: m/z=605 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.81 (dd, 1H), 3.97 (dd, 1H), 4.26 (s, 3H),4.86-4.97 (m, 2H), 5.06 (s, 2H), 6.89 (d, 1H), 7.32 (d, 1H), 7.45-7.52(m, 1H), 7.56-7.65 (m, 3H), 7.69-7.76 (m, 3H), 13.35 (br. s, 1H).

Example 59

LC/MS [Method 2]: R_(t)=2.37 min; MS [ESIpos]: m/z=605 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.79 (dd, 1H), 3.93 (dd, 1H), 4.12 (s, 2H),4.24-4.30 (m, 1H), 5.07-5.22 (m, 4H), 6.89 (d, 1H), 7.40-7.48 (m, 2H),7.55-7.66 (m, 3H), 7.67-7.75 (m, 3H), 13.26 (br. s, 1H).

Example 60[5-(2-Chlorophenyl)-3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1H-1,2,4-triazol-1-yl]aceticacid

65 mg (0.11 mmol) of the compound from Example 56 were dissolved in 5 mlof methanol, and 0.26 ml (0.26 mmol) of a 1 N aqueous lithium hydroxidesolution was added. The mixture was stirred at RT for 30 min. Themixture was then freed from the solvent under reduced pressure, taken upin 10 ml of water and neutralized with 0.85 ml (0.85 mmol) of 1 Nhydrochloric acid. The mixture was extracted twice with in each case 15ml of ethyl acetate. The combined organic phases were dried over sodiumsulfate, filtered and concentrated under reduced pressure. This gave 57mg (76% of theory) of the title compound in a purity of 84%.

LC/MS [Method 4]: R_(t)=0.95 min; MS [ESIpos]: m/z=557 and 559 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.85 (dd, 1H), 3.96-4.03 (m, 1H), 4.24-4.36(m, 1H), 4.86 (s, 2H), 5.03-5.14 (m, 2H), 6.90 (d, 1H), 7.47-7.52 (m,2H), 7.55-7.68 (m, 4H), 7.76 (d, 2H), 13.30 (br. s, 1H).

Example 61[3-(2-Chlorophenyl)-5-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1H-1,2,4-triazol-1-yl]aceticacid

205 mg (0.36 mmol) of the compound from Example 57 were reactedanalogously to the preparation of the compound in Example 60. This gave198 mg (94% of theory) of the title compound in a purity of 93%.

LC/MS [Method 2]: R_(t)=2.20 min; MS [ESIpos]: m/z=557 and 559 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.81 (dd, 1H), 3.96 (dd, 1H), 4.24-4.38 (m,1H), 5.20-5.37 (m, 4H), 6.90 (br. s, 1H), 7.42-7.47 (m, 2H), 7.55-7.58(m, 1H), 7.62 (d, 2H), 7.74 (d, 2H), 7.82-7.87 (m, 1H), 13.38 (br. s,1H).

Example 622-(3-{[3-(4-Chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]methyl}-5-[2-(trifluoromethyl)benzyl]-1H-1,2,4-triazol-1-yl)acetamide(racemate)

85 mg (0.14 mmol) of the compound from Example 58 were initially chargedin 2.5 ml of DMF, and 23 mg (0.17 mmol) of HOBt and 35 mg (0.18 mmol) ofEDC were added. After 20 min of stirring at RT, 0.3 ml (5.65 mmol) ofammonia solution (32% strength in water) was added and the reaction wasstirred at room temperature for 16 h. The reaction solution was thenfreed from excess ammonia under reduced pressure, about 3 ml of waterwere added and the mixture was extracted three times with in each case 5ml of ethyl acetate. The combined organic phases were dried overmagnesium sulfate, filtered and concentrated under reduced pressure. Thecrude product was purified chromatographically [Method 19]. This gave 58mg (69% of theory) of the target compound.

LC/MS [Method 5]: R_(t)=2.22 min; MS [ESIpos]: m/z=604 (M+H)⁺.

By preparative HPLC on a chiral phase [Method 17], the racemate fromExample 62 (58 mg) was separated into the enantiomers. This gave 27 mgof enantiomer 1 (Example 63), which eluted first, and 29 mg ofenantiomer 2 (Example 64), which eluted later:

Example 632-(3-{[3-(4-Chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]methyl}-5-[2-(trifluoromethyl)benzyl]-1H-1,2,4-triazol-1-yl)acetamide(enantiomer 1)

Enantiomer which elutes first in the racemate separation of Example 62.

Chiral HPLC [Method 18]: R_(t)=6.57 min.

¹H-NMR (400 MHz, DMSO-d₆): δ=3.81 (dd, 1H), 3.97 (dd, 1H), 4.22-4.33 (m,3H), 4.83 (s, 2H), 4.85-4.95 (m, 2H), 6.89 (d, 1H), 7.31-7.38 (m, 2H),7.45-7.50 (m, 1H), 7.55-7.64 (m, 3H), 7.65-7.76 (m, 4H).

Example 642-(3-{[3-(4-Chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]methyl}-5-[2-(trifluoromethyl)benzyl]-1H-1,2,4-triazol-1-yl)acetamide(enantiomer 2)

Enantiomer which elutes last in the racemate separation of Example 62.

Chiral HPLC [Method 18]: R_(t)=7.70 min.

¹H-NMR (400 MHz, DMSO-d₆): δ=3.81 (dd, 1H), 3.97 (dd, 1H), 4.22-4.33 (m,3H), 4.83 (s, 2H), 4.85-4.95 (m, 2H), 6.89 (d, 1H), 7.31-7.38 (m, 2H),7.45-7.50 (m, 1H), 7.55-7.64 (m, 3H), 7.65-7.76 (m, 4H).

Example 652-(5-{[3-(4-Chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]methyl}-3-[2-(trifluoromethyl)benzyl]-1H-1,2,4-triazol-1-yl)acetamide(racemate)

95 mg (0.16 mmol) of the compound from Example 59 were initially chargedin 2.5 ml of DMF, and 25 mg (0.19 mmol) of HOBt and 39 mg (0.20 mmol) ofEDC were added. After 20 min of stirring at RT, 0.3 ml (5.65 mmol) ofammonia solution (32% strength in water) was added, and the reaction wasstirred at room temperature for 16 h. The reaction solution was thenfreed from excess ammonia under reduced pressure, about 3 ml of waterwere added and the mixture was extracted three times with in each case 5ml of ethyl acetate. The combined organic phases were dried overmagnesium sulfate, filtered and concentrated under reduced pressure. Thecrude product was purified chromatographically [Method 19]. This gave 58mg (61% of theory) of the target compound.

LC/MS [Method 5]: R_(t)=2.32 min; MS [ESIpos]: m/z=604 (M+H)⁺.

By preparative HPLC on a chiral phase [Method 12], the racemate fromExample 65 (58 mg) was separated into the enantiomers. This gave 28 mgof enantiomer 1 (Example 66), which eluted first, and 28 mg ofenantiomer 2 (Example 67), which eluted later:

Example 662-(5-{[3-(4-Chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]methyl}-3-[2-(trifluoromethyl)benzyl]-1H-1,2,4-triazol-1-yl)acetamide(enantiomer 1)

Enantiomer which elutes first in the racemate separation of Example 65.

Chiral HPLC [Method 13]: R_(t)=4.78 min.

¹H-NMR (400 MHz, DMSO-d₆): δ=3.79 (dd, 1H), 3.94 (dd, 1H), 4.10 (s, 2H),4.24-4.35 (m, 1H), 4.93 (s, 2H), 5.09-5.19 (m, 2H), 6.87 (d, 1H), 7.34(s, 1H), 7.40-7.48 (m, 2H), 7.55-7.75 (m, 7H).

Example 672-(5-{[3-(4-Chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]methyl}-3-[2-(trifluoromethyl)benzyl]-1H-1,2,4-triazol-1-yl)acetamide(enantiomer 2)

Enantiomer which elutes last in the racemate separation of Example 65.

Chiral HPLC [Method 13]: R_(t)=6.35 min.

¹H-NMR (400 MHz, DMSO-d₆): δ=3.79 (dd, 1H), 3.94 (dd, 1H), 4.10 (s, 2H),4.24-4.35 (m, 1H), 4.93 (s, 2H), 5.09-5.19 (m, 2H), 6.87 (d, 1H), 7.34(s, 1H), 7.40-7.48 (m, 2H), 7.55-7.75 (m, 7H).

Example 682-[5-(2-Chlorophenyl)-3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1H-1,2,4-triazol-1-yl]acetamide

54 mg (0.10 mmol) of the compound from Example 60 were initially chargedin 4 ml of DMF, and 19 mg (0.13 mmol) of HOBt and 24 mg (0.03 mmol) ofEDC were added. After 10 min of stirring at RT, 0.1 ml (1.93 mmol) ofammonia solution (32% strength in water) were added and the mixture wasstirred at room temperature for 16 h. The reaction solution was thenfreed from excess ammonia under reduced pressure, about 3 ml of waterwere added and the mixture was extracted three times with in each case 5ml of ethyl acetate. The combined organic phases were dried overmagnesium sulfate, filtered and concentrated under reduced pressure. Thecrude product was purified chromatographically [Method 19]. This gave 27mg (46% of theory) of the target compound.

LC/MS [Method 3]: R_(t)=1.08 min; MS [ESIpos]: m/z=556 and 558 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.85 (dd, 1H), 4.00 (dd, 1H), 4.25-4.37 (m,1H), 4.64 (s, 2H), 5.07 (s, 2H), 6.91 (d, 1H), 7.24 (br. s, 1H),7.46-7.67 (m, 7H), 7.76 (d, 2H).

Example 692-[3-(2-Chlorophenyl)-5-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1H-1,2,4-triazol-1-yl]acetamide

100 mg (0.18 mmol) of the compound from Example 61 were reactedanalogously to the preparation of the compound in Example 68. This gave67 mg (67% of theory) of the title compound.

LC/MS [Method 3]: R_(t)=1.14 min; MS [ESIpos]: m/z=556 and 558 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.81 (dd, 1H), 3.96 (dd, 1H), 4.28-4.34 (m,1H), 5.04-5.14 (m, 2H), 5.22-5.32 (m, 2H), 6.86 (d, 1H), 7.39-7.46 (m,2H), 7.52-7.57 (m, 1H), 7.62 (d, 2H), 7.72-7.78 (m, 3H), 7.83-7.88 (m,1H), 7.95 (s, 1H).

Example 705-(4-Chlorophenyl)-2-{[5-(2-chlorophenyl)-4H-1,2,4-triazol-3-yl]methyl}-4-(3,3,3-trifluoropropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

50 mg (0.14 mmol) of the compound from Example 23A were reactedanalogously to the preparation of the compound in Example 54. This gave8 mg (11% of theory) of the title compound.

LC/MS [Method 4]: R_(t)=1.06 min; MS [ESIpos]: m/z=483 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=2.59-2.69 (m, 2H), 4.00 (t, 2H), 5.13 (s,2H), 7.42-7.51 (m, 2H), 7.56-7.71 (m, 5H), 7.75-7.81 (m, 1H), 14.25 (br.s, 1H).

Example 715-(4-Chlorophenyl)-2-{[5-(2,6-dichlorobenzyl)-4H-1,2,4-triazol-3-yl]methyl}-4-(3,3,3-trifluoropropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

50 mg (0.14 mmol) of the compound from Example 23A were reactedanalogously to the preparation of the compound in Example 54. This gave18 mg (25% of theory) of the title compound.

LC/MS [Method 4]: R_(t)=1.10 min; MS [ESIpos]: m/z=531 and 533 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=2.55-2.69 (m, 2H), 3.97 (t, 2H), 4.23-4.34(m, 2H), 4.95 (s, 2H), 7.31-7.37 (m, 1H), 7.48 (d, 2H), 7.60-7.68 (m,4H), 13.70 (br. s, 1H).

Example 722-{[5-(2-Chlorobenzyl)-4H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-(3,3,3-trifluoropropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

48 mg (0.13 mmol) of the compound from Example 23A were reactedanalogously to the preparation of the compound in Example 54. This gave22 mg (33% of theory) of the title compound.

LC/MS [Method 4]: R_(t)=1.07 min; MS [ESIpos]: m/z=497 and 499 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=2.56-2.69 (m, 2H), 3.98 (t, 2H), 4.12 (s,2H), 4.97 (s, 2H), 7.25-7.34 (m, 3H), 7.40-7.46 (m, 1H), 7.59-7.68 (m,5H).

Example 735-(4-Chlorophenyl)-2-{[5-(2-chlorophenyl)-2-thienyl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

85 mg (0.28 mmol) of the compound from Example 5A and 134 mg (0.41 mmol)of cesium carbonate were suspended in 5 ml of acetonitrile, and 113 mg(0.28 mmol) of the compound from Example 56A were added. The mixture wasstirred under reflux for 20 h. For work-up, the mixture was cooled toRT, the acetonitrile was removed under reduced pressure and 10 ml ofwater were added to the residue. The mixture was extracted twice with ineach case 10 ml of ethyl acetate. The combined organic phases were driedover sodium sulfate, filtered and concentrated under reduced pressure.The crude product was purified chromatographically [Method 19]. Thisgave 4 mg (3% of theory) of the target compound.

LC/MS [Method 4]: R_(t)=1.32 min; MS [ESIpos]: m/z=514 and 516 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.83 (dd, 1H), 4.00 (dd, 1H), 4.22-4.35 (m,1H), 5.16-5.26 (m, 2H), 6.91 (br. s, 1H), 7.16 (d, 1H), 7.32 (d, 1H),7.34-7.44 (m, 2H), 7.53-7.65 (m, 4H), 7.76 (d, 2H).

Example 745-(4-Chlorophenyl)-2-{[5-(2,3-dichlorophenyl)-2-thienyl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

67 mg (0.22 mmol) of the compound from Example 5A and 142 mg (0.44 mmol)of cesium carbonate were suspended in 4 ml of acetonitrile, and 70 mg(0.28 mmol) of the compound from Example 57A were added. The mixture wasstirred under reflux for 2 h. For work-up, the mixture was cooled to RT,the acetonitrile was removed under reduced pressure and 10 ml of waterwere added to the residue. The mixture was extracted twice with in eachcase 10 ml of ethyl acetate. The combined organic phases were dried oversodium sulfate, filtered and concentrated under reduced pressure. Thecrude product was purified chromatographically [Method 19]. This gave 29mg (24% of theory) of the target compound.

LC/MS [Method 4]: R_(t)=1.37 min; MS [ESIpos]: m/z=548 and 550 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.83 (dd, 1H), 3.99 (dd, 1H), 4.24-4.34 (m,1H), 5.18-5.27 (m, 2H), 6.90 (d, 1H), 7.17 (d, 1H), 7.33 (d, 1H), 7.42(t, 1H), 7.57 (dd, 1H), 7.61-7.67 (m, 3H), 7.74-7.79 (m, 2H).

Example 755-(4-Chlorophenyl)-2-{[5-(2,3-difluorophenyl)-2-thienyl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

Under an atmosphere of argon, 84 mg (0.19 mmol) of the compound fromExample 30A and 45 mg (0.29 mmol) of 2,3-difluorophenylboronic acid weredissolved in 2 ml of toluene. 9 mg (0.01 mmol) oftris(dibenzylideneacetone)dipalladium, 8 mg (0.02 mmol) of2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl and 81 mg (0.38mmol) of potassium phosphate were then added, and under argon themixture was heated at 110° C. for 14 h. For work-up, the mixture wasdiluted at RT with 10 ml of ethyl acetate and 10 ml of water, theorganic phase was separated off and the aqueous phase was extracted twomore times with in each case 10 ml of ethyl acetate. The combinedorganic phases were dried over sodium sulfate, filtered and concentratedunder reduced pressure. The crude product was purifiedchromatographically [Method 19]. This gave 25 mg (24% of theory) of thetarget compound.

LC/MS [Method 2]: R_(t)=2.72 min; MS [ESIpos]: m/z=516 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.78-4.07 (m, 2H), 4.23-4.39 (m, 1H),5.10-5.26 (m, 2H), 6.86-6.95 (m, 1H), 6.99-7.05 (m, 1H), 7.17-7.59 (m,4H), 7.60-7.66 (m, 1H), 7.73-7.80 (m, 2H), 7.83-7.90 (m, 1H).

Example 765-(4-Chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2-({2-[2-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

Under an atmosphere of argon, 62 mg (0.14 mmol) of the compound fromExample 31A and 40 mg (0.21 mmol) of 2-(trifluoromethyl)phenylboronicacid were dissolved in 2 ml of toluene. 6.5 mg (0.007 mmol) oftris(dibenzylideneacetone)dipalladium, 5.6 mg (0.014 mmol) of2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl and 60 mg (0.28mmol) of potassium phosphate were then added, and under argon themixture was heated to 110° C. for 48 h. For work-up, the mixture wasdiluted at RT with 10 ml of ethyl acetate and 10 ml of water, theorganic phase was separated off and the aqueous phase was extracted twomore times with in each case 10 ml of ethyl acetate. The combinedorganic phases were dried over sodium sulfate, filtered and concentratedunder reduced pressure. The crude product was purifiedchromatographically [Method 19]. This gave 10 mg (13% of theory) of thetarget compound.

LC/MS [Method 2]: R_(t)=2.54 min; MS [ESIpos]: m/z=549 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.83 (dd, 1H), 4.00 (dd, 1H), 4.22-4.34 (m,1H), 5.29-5.38 (m, 2H), 6.90 (d, 1H), 7.61-7.67 (m, 2H), 7.71-7.83 (m,5H), 7.93 (d, 1H), 7.96 (s, 1H).

Example 775-(4-Chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2-({5-[2-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

40 mg (0.13 mmol) of the compound from Example 5A were dissolved in 7 mlof acetonitrile, and 66 mg (0.20 mmol) of cesium carbonate and 42 mg(0.13 mmol) of the compound from Example 89A were added. The mixture wasstirred at 80° C. for 1 h. For work-up, the mixture was cooled to RT,diluted with 5 ml of methanol and filtered. The filtrate wasconcentrated under reduced pressure and the crude product was thenpurified chromatographically [Method 19]. This gave 47 mg (66% oftheory) of the target compound.

LC/MS [Method 3]: R_(t)=2.48 min; MS [ESIpos]: m/z=549 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.86 (dd, 1H), 4.02 (dd, 1H), 4.24-4.34 (m,1H), 5.35-5.45 (m, 2H), 6.92 (s, 1H), 7.58-7.66 (m, 3H), 7.66-7.80 (m,5H), 7.90 (d, 1H).

Example 785-(4-Chlorophenyl)-2-{[5-(2-chlorophenyl)-1,3-thiazol-2-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

70 mg (0.23 mmol) of the compound from Example 5A were reacted with 66mg (0.23 mmol) of the compound from Example 88A analogously to thepreparation of the compound in Example 77. This gave 65 mg (55% oftheory) of the title compound.

LC/MS [Method 4]: R_(t)=1.23 min; MS [ESIpos]: m/z=515 and 517 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.86 (dd, 1H), 4.02 (dd, 1H), 4.24-4.35 (m,1H), 5.39 (s, 2H), 6.92 (br. s, 1H), 7.44 (dd, 2H), 7.58-7.72 (m, 4H),7.78 (d, 2H), 8.06 (s, 1H).

Example 792-{[5-(3-Chloro-2-fluorophenyl)-1,3-thiazol-2-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

70 mg (0.23 mmol) of the compound from Example 5A were reacted with 70mg (0.23 mmol) of the compound from Example 90A analogously to thepreparation of the compound in Example 77. This gave 90 mg (72% oftheory) of the title compound.

LC/MS [Method 3]: R_(t)=1.44 min; MS [ESIpos]: m/z=533 and 535 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.86 (dd, 1H), 4.02 (dd, 1H), 4.25-4.35 (m,1H), 5.37-5.43 (m, 2H), 6.92 (s, 1H), 7.30-7.36 (m, 1H), 7.60-7.67 (m,3H), 7.75-7.82 (m, 3H), 8.27 (s, 1H).

Example 805-(4-Chlorophenyl)-2-({5-[2-fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

55 mg (0.18 mmol) of the compound from Example 5A were reacted with 61mg (0.18 mmol) of the compound from Example 91A analogously to thepreparation of the compound in Example 77. This gave 55 mg (52% oftheory) of the title compound.

LC/MS [Method 4]: R_(t)=1.26 min; MS [ESIpos]: m/z=567 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.86 (dd, 1H), 4.02 (dd, 1H), 4.25-4.35 (m,1H), 5.41 (s, 2H), 6.92 (s, 1H), 7.52 (t, 1H), 7.64 (d, 2H), 7.75-7.84(m, 3H), 8.17 (t, 1H), 8.33 (s, 1H).

Example 815-(4-Chlorophenyl)-2-{[5-(2-chlorophenyl)-4-(trifluoromethyl)-1,3-thiazol-2-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

40 mg (0.13 mmol) of the compound from Example 5A were reacted with 46mg (0.13 mmol) of the compound from Example 92A analogously to thepreparation of the compound in Example 77. This gave 58 mg (76% oftheory) of the title compound.

LC/MS [Method 4]: R_(t)=1.32 min; MS [ESIpos]: m/z=583 and 585 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.86 (dd, 1H), 4.02 (dd, 1H), 4.24-4.34 (m,1H), 5.44-5.49 (m, 2H), 6.90 (br. s, 1H), 7.44-7.50 (m, 1H), 7.53-7.60(m, 2H), 7.61-7.68 (m, 3H), 7.75-7.80 (m, 2H).

Example 825-(4-Chlorophenyl)-2-{[2-(2-chlorophenyl)-1,3-oxazol-5-yl]methyl}-4-[(2,S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

113 mg (0.37 mmol) of the compound from Example 5A were reacted with 100mg (0.37 mmol) of the compound from Example 54A analogously to thepreparation of the compound in Example 77. This gave 23 mg (12% oftheory) of the title compound.

LC/MS [Method 6]: R_(t)=2.44 min; MS [ESIpos]: m/z=499 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.82 (dd, 1H), 3.98 (dd, 1H), 4.25-4.33 (m,1H), 5.15-5.25 (m, 2H), 6.88 (d, 1H), 7.41 (s, 1H), 7.48-7.57 (m, 2H),7.60-7.66 (m, 3H), 7.72-7.76 (m, 2H), 7.92 (dd, 1H).

Example 835-(4-Chlorophenyl)-2-{[2-(2,3-dichlorophenyl)-1,3-oxazol-5-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

49 mg (0.16 mmol) of the compound from Example 5A were reacted with 49mg (0.16 mmol) of the compound from Example 55A analogously to thepreparation of the compound in Example 77. This gave 35 mg (40% oftheory) of the title compound.

LC/MS [Method 4]: R_(t)=1.23 min; MS [ESIpos]: m/z=533 and 535 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.82 (dd, 1H), 3.98 (dd, 1H), 4.22-4.34 (m,1H), 5.17-5.26 (m, 2H), 6.89 (s, 1H), 7.45 (s, 1H), 7.53 (t, 1H),7.61-7.65 (m, 2H), 7.72-7.76 (m, 2H), 7.84 (dd, 1H), 7.88 (dd, 1H).

Example 84 5-(4-Chlorophenyl)-4-cyclopropyl-24{5-[3-(trifluoromethyl)benzyl]-1,3-thiazol-2-yl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

52 mg (0.11 mmol) of the compound from Example 27A and 47 mg (0.12 mmol)of 4-methoxy-phenyldithiophosphonic anhydride (Lawesson reagent) weredissolved in 1 ml of THF, and the mixture was stirred at 70° C. for 16h. After cooling to RT, the mixture was partitioned between 10 ml oftert-butyl methyl ether and 10 ml of water. The organic phase wasseparated off, washed with in each case 10 ml of water and saturatedsodium chloride solution, dried over sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified bypreparative HPLC [Method 19]. This gave 50 mg (97% of theory) of thetitle compound as a colorless solid.

MS [ESIpos]: m/z=491 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=0.71-0.81 (m, 2H), 0.97-1.06 (m, 2H),2.94-3.03 (m, 1H), 4.18 (s, 2H), 5.25 (s, 2H), 7.35-7.55 (m, 6H), 7.69(d, 2H).

Example 855-(4-Chlorophenyl)-4-cyclopropyl-2-({5-[3-(trifluoromethyl)benzyl]-1H-imidazol-2-yl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

50 mg (0.10 mmol) of the compound from Example 27A were dissolved in 1ml of DMF and mixed with 23 mg (0.30 mmol) of ammonium acetate, and themixture was stirred in a microwave oven at 200° C. for 15 min Aftercooling, a further 30 mg (0.39 mmol) of ammonium acetate were added, andthe mixture was stirred in a microwave oven at 200° C. for another 30min After cooling to RT, the mixture was partitioned between 10 ml ofethyl acetate and 10 ml of water. The organic phase was separated off,washed with in each case 10 ml of water and saturated sodium chloridesolution, dried over sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by preparative HPLC [Method19]. This gave 17 mg (35% of theory) of the target compound as ayellowish resin.

MS [ESIpos]: m/z=474 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=0.65-0.82 (br. m, 2H), 0.97-1.09 (m, 2H),2.92-3.03 (m, 1H), 3.98 (s, 2H), 5.10 (s, 2H), 7.33-7.58 (m, 6H), 7.68(d, 2H), 10.19 (s, 1H).

Example 865-(4-Chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2-({5-[2-(trifluoromethyl)phenyl]pyridin-3-yl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

72 mg (0.15 mmol) of the compound from Example 28A and 43 mg (0.23 mmol)of 2-(trifluoro-methyl)phenylboronic acid were dissolved in 2 ml ofdioxane. For 10 min, a stream of argon was passed through this solution,and 8.7 mg (0.008 mmol) of tetrakis(triphenylphosphine)palladium(0) werethen added under argon. The mixture was heated to the boil, and 0.15 ml(0.30 mmol) of a 2 N aqueous sodium carbonate solution was added underargon. The mixture was stirred under reflux for 20 h. After cooling toRT, the mixture was diluted with 10 ml of water and extracted twice within each case 15 ml of ethyl acetate. The combined organic phases weredried over magnesium sulfate, filtered and concentrated under reducedpressure. The crude product was purified chromatographically [Method19]. This gave 36 mg (44% of theory) of the target compound.

LC/MS [Method 4]: R_(t)=1.18 min; MS [ESIpos]: m/z=543 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.83 (dd, 1H), 3.99 (dd, 1H), 4.23-4.35 (m,1H), 5.09-5.20 (m, 2H), 6.90 (d, 1H), 7.47 (d, 1H), 7.59-7.65 (m, 2H),7.65-7.81 (m, 5H), 7.89 (d, 1H), 8.49 (d, 1H), 8.62 (d, 1H).

Example 875-(4-Chlorophenyl)-2-{[5-(2-chlorophenyl)pyridin-3-yl]methyl}-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

Analogously to the preparation of the compound in Example 86, 72 mg(0.15 mmol) of the compound from Example 28A and 59 mg (0.23 mmol) of2-chlorophenylboronic acid were reacted with one another. This gave 49mg (64% of theory) of the target compound.

LC/MS [Method 4]: R_(t)=1.16 min; MS [ESIpos]: m/z=509 and 511 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.83 (dd, 1H), 3.99 (dd, 1H), 4.24-4.36 (m,1H), 5.10-5.20 (m, 2H), 6.90 (d, 1H), 7.44-7.50 (m, 3H), 7.58-7.65 (m,3H), 7.75 (d, 2H), 7.86 (t, 1H), 8.57-8.62 (m, 2H).

Example 885-(4-Chlorophenyl)-2-{[5-(2,3-dichlorophenyl)pyridin-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

Analogously to the preparation of the compound in Example 86, 34 mg(0.07 mmol) of the compound from Example 29A and 20 mg (0.10 mmol) of2,3-dichlorophenylboronic acid were reacted with one another. This gave26 mg (69% of theory) of the target compound.

LC/MS [Method 4]: R_(t)=1.21 min; MS [ESIpos]: m/z=543 and 545 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.83 (dd, 1H), 3.99 (dd, 1H), 4.26-4.34 (m,1H), 5.10-5.20 (m, 2H), 6.90 (d, 1H), 7.42-7.53 (m, 2H), 7.60-7.65 (m,2H), 7.71-7.78 (m, 3H), 7.86 (t, 1H), 8.61 (dd, 2H).

Example 895-(4-Chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2-({2-[2-(trifluoromethyl)phenyl]-pyridin-4-yl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

145 mg (0.46 mmol) of the compound from Example 64A were dissolved in 3ml of acetonitrile, and 141 mg (0.46 mmol) of the compound from Example5A and 224 mg (0.69 mmol) of cesium carbonate were added. The mixturewas stirred at 60° C. for 16 h. After cooling to RT, the solid wasfiltered off and rinsed with a little acetonitrile. Under reducedpressure, the filtrate was reduced to a volume of about 2 ml, 0.1 ml of1 N hydrochloric acid was added and the product was directly purifiedchromatographically [Method 19]. This gave 49 mg (20% of theory) of thetarget compound.

LC/MS [Method 4]: R_(t)=1.15 min; MS [ESIpos]: m/z=543 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.85 (dd, 1H), 4.01 (dd, 2H), 4.28-4.35 (m,1H), 5.09-5.20 (m, 2H), 6.90 (d, 1H), 7.32 (dd, 1H), 7.41 (s, 1H), 7.52(d, 1H), 7.61-7.66 (m, 2H), 7.68 (d, 1H), 7.73-7.79 (m, 3H), 7.85 (d,1H), 8.63 (d, 1H).

Example 905-(4-Chlorophenyl)-2-{[2-(2-chlorophenyl)pyridin-4-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

Analogously to the preparation of the compound in Example 89, 261 mg(0.85 mmol) of the compound from Example 5A and 240 mg (0.85 mmol) ofthe compound from Example 65A were reacted with one another. This gave249 mg (54% of theory) of the target compound.

LC/MS [Method 3]: R_(t)=1.28 min; MS [ESIpos]: m/z=509 and 511 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.87 (dd, 1H), 4.01 (dd, 1H), 4.26-4.39 (m,1H), 5.10-5.20 (m, 2H), 6.90 (d, 1H), 7.30 (d, 1H), 7.41-7.50 (m, 2H),7.55-7.60 (m, 3H), 7.64 (d, 2H), 7.77 (d, 2H), 8.68 (d, 1H).

Example 915-(4-Chlorophenyl)-2-{[2-(2,3-dichlorophenyl)pyridin-4-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

81 mg (0.26 mmol) of the compound from Example 66A were dissolved in 3ml of acetonitrile and 79 mg (0.26 mmol) of the compound from Example 5Aand 125 mg (0.38 mmol) of cesium carbonate were added. The mixture wasstirred at 65° C. for 2 h and at RT for a further 16 h. The solid wasthen filtered off and rinsed with a little acetonitrile. The filtratewas concentrated under reduced pressure and directly purifiedchromatographically [Method 19]. This gave 79 mg (56% of theory) of thetarget compound.

LC/MS [Method 4]: R_(t)=1.21 min; MS [ESIpos]: m/z=543 and 545 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.85 (dd, 1H), 4.01 (dd, 1H), 4.28-4.35 (m,1H), 5.10-5.21 (m, 2H), 6.91 (d, 1H), 7.34 (dd, 1H), 7.45-7.52 (m, 2H),7.57 (s, 1H), 7.61-7.66 (m, 2H), 7.71-7.79 (m, 3H), 8.67 (d, 1H).

Example 925-(4-Chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2-({2-[2-(trifluoromethyl)phenyl]-pyrimidin-4-yl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

303 mg (0.19 mmol) of the compound from Example 80A (purity about 20%)were dissolved in 2 ml of acetonitrile, and 65 mg (0.21 mmol) of thecompound from Example 5A and 93 mg (0.29 mmol) of cesium carbonate wereadded. The mixture was stirred at 60° C. for 2.5 h and at RT for afurther 96 h. The solid was then filtered off and rinsed with a littleacetonitrile. The filtrate was concentrated under reduced pressure anddirectly purified chromatographically [Method 19]. This gave 19 mg ofthe target compound, which were subjected to a further chromatographicpurification on silica gel (mobile phase: cyclohexane/ethyl acetate 7:3,then 1:1). This gave 8 mg (7% of theory) of the target compound.

LC/MS [Method 3]: R_(t)=1.32 min; MS [ESIpos]: m/z=544 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.86 (dd, 1H), 4.01 (dd, 1H), 4.31-4.35 (m,1H), 5.13-5.26 (m, 2H), 6.93 (d, 1H), 7.39 (d, 1H), 7.61-7.67 (m, 2H),7.69-7.83 (m, 5H), 7.88 (d, 1H), 8.93 (d, 1H).

Example 935-(4-Chlorophenyl)-2-{[2-(2-chlorophenyl)pyrimidin-4-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

259 mg (0.18 mmol) of the compound from Example 81A (purity about 20%)were dissolved in 2 ml of acetonitrile, and 62 mg (0.21 mmol) of thecompound from Example 5A and 89 mg (0.27 mmol) of cesium carbonate wereadded. The mixture was stirred at 60° C. for 2.5 h and at RT for afurther 96 h. The solid was then filtered off and rinsed with a littleacetonitrile. The filtrate was concentrated under reduced pressure anddirectly purified chromatographically [Method 19]. This gave 31 mg ofthe target compound, which were subjected to a further chromatographicpurification on silica gel (mobile phase: cyclohexane/ethyl acetate 7:3,then 1:1). This gave 23 mg (22% of theory) of the target compound.

LC/MS [Method 4]: R_(t)=1.13 min; MS [ESIpos]: m/z=510 and 512 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.87 (dd, 1H), 4.02 (dd, 1H), 4.28-4.38 (m,1H), 5.16-5.26 (m, 2H), 6.93 (d, 1H), 7.36 (d, 1H), 7.44-7.54 (m, 2H),7.56-7.60 (m, 1H), 7.61-7.66 (m, 2H), 7.71-7.79 (m, 3H), 8.94 (d, 1H).

Example 945-(4-Chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2-({6-[2-(trifluoromethyl)phenyl]-pyrimidin-4-yl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

37 mg (0.12 mmol) of the compound from Example 82A were dissolved in 2ml of acetonitrile, and 39 mg (0.13 mmol) of the compound from Example5A and 57 mg (0.18 mmol) of cesium carbonate were added. The mixture wasstirred at 60° C. for 2.5 h. After cooling to RT, the solid was filteredoff and rinsed with a little acetonitrile. The filtrate was concentratedunder reduced pressure and directly purified chromatographically [Method19]. The product obtained was subjected to a further chromatographicpurification on silica gel (mobile phase: cyclohexane/ethyl acetate 4:1,then 3:2). This gave 28 mg (41% of theory) of the target compound.

LC/MS [Method 6]: R_(t)=2.34 min; MS [ESIpos]: m/z=544 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.86 (dd, 1H), 4.01 (dd, 1H), 4.27-4.34 (m,1H), 5.17-5.29 (m, 2H), 6.91 (d, 1H), 7.55 (s, 1H), 7.59 (d, 1H), 7.63(d, 2H), 7.72-7.78 (m, 3H), 7.80-7.85 (m, 1H), 7.91 (d, 1H), 9.24 (d,1H).

Example 955-(4-Chlorophenyl)-2-{[6-(2-chlorophenyl)pyrimidin-4-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

Analogously to the preparation of the compound in Example 94, 27 mg(0.10 mmol) of the compound from Example 83A and 32 mg (0.11 mmol) ofthe compound from Example 5A were reacted with one another. This gave 29mg (54% of theory) of the target compound.

LC/MS [Method 4]: R_(t)=1.15 min; MS [ESIpos]: m/z=510 and 512 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.86 (dd, 1H), 4.02 (dd, 1H), 4.27-4.35 (m,1H), 5.19-5.29 (m, 2H), 6.91 (d, 1H), 7.48-7.59 (m, 2H), 7.60-7.69 (m,4H), 7.72 (d, 1H), 7.74-7.80 (m, 2H), 9.27 (d, 1H).

Example 965-(4-Chlorophenyl)-2-{[6-(2,3-dichlorophenyl)pyrimidin-4-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

Analogously to the preparation of the compound in Example 94, 23 mg(0.07 mmol) of the compound from Example 84A and 24 mg (0.08 mmol) ofthe compound from Example 5A were reacted with one another. This gave 29mg (66% of theory) of the target compound.

LC/MS [Method 6]: R_(t)=2.54 min; MS [ESIpos]: m/z=544 and 546 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.86 (dd, 1H), 4.02 (dd, 1H), 4.26-4.38 (m,1H), 5.18-5.30 (m, 2H), 6.92 (s, 1H), 7.51-7.56 (m, 1H), 7.57-7.60 (m,1H), 7.61-7.65 (m, 2H), 7.71 (d, 1H), 7.74-7.79 (m, 2H), 7.81 (dd, 1H),9.29 (d, 1H).

Example 975-(4-Chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2-({1-[3-(trifluoromethyl)benzyl]-1H-1,2,3-triazol-4-yl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

29 mg (0.12 mmol) of 3-(trifluoromethyl)benzyl bromide were initiallycharged in 1 ml of acetonitrile, and 8 mg (0.12 mmol) of sodium azidewere added. The mixture was stirred at RT for 1 h. 0.24 mg (0.012 mmol)of copper(II) acetate monohydrate and 50 mg (0.14 mmol) of the compoundfrom Example 13A were then added. The resulting mixture was stirred atroom temperature for 11 days. The reaction mixture was then filteredthrough a little silica gel, the product being eluted with about 10 mlof ethyl acetate, and the filtrate was concentrated under reducedpressure. The crude product was purified chromatographically [Method19]. This gave 52 mg (65% of theory) of the target compound.

LC/MS [Method 4]: R_(t)=1.13 min; MS [ESIpos]: m/z=547 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=3.91-3.99 (m, 1H), 3.98-4.05 (m, 1H),4.46-4.56 (m, 1H), 5.15 (q, 2H), 5.34 (d, 1H), 5.51-5.61 (m, 2H),7.41-7.59 (m, 8H), 7.63 (d, 1H).

Example 985-(4-Chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2-({1-[2-(trifluoromethyl)benzyl]-1H-1,2,3-triazol-4-yl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

Analogously to the preparation of the compound in Example 97, 50 mg(0.14 mmol) of the compound from Example 13A gave 54 mg (68% of theory)of the title compound.

LC/MS [Method 4]: R_(t)=1.13 min; MS [ESIpos]: m/z=547 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=3.91-3.99 (m, 1H), 3.99-4.06 (m, 1H),4.46-4.57 (m, 1H), 5.16 (q, 2H), 5.31 (d, 1H), 5.72 (s, 2H), 7.20 (d,1H), 7.42-7.58 (m, 7H), 7.72 (d, 1H).

Example 995-(4-Chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2-({1-[2-(trifluoromethyl)phenyl]-1H-1,2,3-triazol-4-yl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

20 mg (0.31 mmol) of sodium azide were initially charged in 1 ml ofmethanol, and 58 mg (0.31 mmol) of 2-(trifluoromethyl)phenylboronic acidand 6 mg (0.03 mmol) of copper(II) acetate monohydrate were added. Themixture was stirred at RT for 18 h. 0.9 ml of water, 30 mg (0.15 mmol)of L-ascorbic acid sodium salt and 117 mg (0.34 mmol) of the compoundfrom Example 14A were then added to the mixture. The mixture was stirredat RT for a further 18 h. For work-up, the mixture was diluted with 10ml of water and 10 ml of ethyl acetate, and 5 ml 0.1 N aqueous sodiumhydroxide solution were added with stirring. After phase separation, theaqueous phase was extracted three more times with in each case 10 ml ofethyl acetate. The combined organic phases were dried over sodiumsulfate, filtered and concentrated under reduced pressure. The crudeproduct was purified by chromatography on silica gel (mobile phase:cyclohexane/ethyl acetate 5:1, then 1:2). This gave 117 mg (71% oftheory) of the target compound.

LC/MS [Method 3]: R_(t)=1.26 min; MS [ESIpos]: m/z=533 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.83 (dd, 1H), 3.99 (dd, 1H), 4.28-4.34 (m,1H), 5.12-5.23 (m, 2H), 6.91 (d, 1H), 7.63 (d, 2H), 7.68-7.79 (m, 3H),7.81-7.96 (m, 2H), 8.03 (d, 1H), 8.51 (s, 1H).

Example 1005-(4-Chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2-({1-[3-(trifluoromethyl)phenyl]-1H-1,2,3-triazol-4-yl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

Analogously to the preparation of the compound in Example 99, 117 mg(0.34 mmol) of the compound from Example 14A gave 138 mg (84% of theory)of the title compound.

LC/MS [Method 3]: R_(t)=1.33 min; MS [ESIpos]: m/z=533 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.83 (dd, 1H), 3.99 (dd, 1H), 4.27-4.38 (m,1H), 5.13-5.22 (m, 2H), 6.91 (d, 1H), 7.59-7.65 (m, 2H), 7.73-7.79 (m,2H), 7.81-7.90 (m, 2H), 8.24-8.32 (m, 2H), 9.02 (s, 1H).

Example 1015-(4-Chlorophenyl)-2-{[1-(2-chlorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

Analogously to the preparation of the compound in Example 99, 75 mg(0.22 mmol) of the compound from Example 14A gave 56 mg (55% of theory)of the title compound.

LC/MS [Method 4]: R_(t)=1.09 min; MS [ESIpos]: m/z=499 and 501 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.83 (dd, 1H), 3.99 (dd, 1H), 4.28-4.35 (m,1H), 5.13-5.22 (m, 2H), 6.91 (d, 1H), 7.55-7.70 (m, 5H), 7.74-7.80 (m,3H), 8.54 (s, 1H).

Example 1025-(4-Chlorophenyl)-2-{[1-(2,3-dichlorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

124 mg (0.36 mmol) of the compound from Example 14A were dissolved in 2ml of acetonitrile, and 0.6 mg (0.003 mmol) of copper(II) acetatemonohydrate and 56 mg (0.30 mmol) of 1-azido-2,3-dichlorobenzene wereadded. The mixture was stirred at 50° C. for 2 h. For work-up, the crudemixture was allowed to cool to RT and filtered through a little silicagel. The product was eluted with ethyl acetate and the solution obtainedwas concentrated under reduced pressure. The crude product was thenpurified by chromatography on silica gel (mobile phase:cyclohexane/ethyl acetate 1:1). This gave 61 mg (31% of theory) of thetarget compound.

LC/MS [Method 4]: R_(t)=1.13 min; MS [ESIpos]: m/z=533 and 535 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.83 (dd, 1H), 3.99 (dd, 1H), 4.29-4.34 (m,1H), 5.13-5.23 (m, 2H), 6.91 (d, 1H), 7.58-7.66 (m, 3H), 7.69 (dd, 1H),7.77 (d, 2H), 7.92 (dd, 1H), 8.59 (s, 1H).

Example 103Methyl(2-chlorophenyl)[4-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1H-1,2,3-triazol-1-yl]acetate

361 mg (1.37 mmol) of methyl bromo(2-chlorophenyl)acetate were initiallycharged in 10 ml of acetonitrile, and 89 mg (1.37 mmol) of sodium azidewere added. The mixture was stirred at RT for 1 h. 2.7 mg (0.14 mmol) ofcopper(II) acetate monohydrate and 569 mg (1.64 mmol) of the compoundfrom Example 14A were then added. The resulting mixture was stirred at50° C. for 48 h. The reaction mixture was then filtered through a littlesilica gel, the product being eluted with about 10 ml of ethyl acetate,and the filtrate was concentrated under reduced pressure. The crudeproduct was purified by chromatography on silica gel (mobile phase:cyclohexane/ethyl acetate 8:1→6:1→4:1→2:1→1:1). This gave 496 mg (53% oftheory) of the target compound.

LC/MS [Method 4]: R_(t)=1.13 min; MS [ESIpos]: m/z=571 and 573 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.76 (s, 3H), 3.81 (dd, 1H), 3.96 (dd, 1H),4.25-4.32 (m, 1H), 5.02-5.12 (m, 2H), 6.88 (dd, 1H), 7.12 (s, 1H),7.39-7.51 (m, 3H), 7.57 (d, 1H), 7.62 (d, 2H), 7.72 (d, 2H), 8.25 (d,1H).

Example 104 (2-Chlorophenyl)[4-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1H-1,2,3-triazol-1-yl]aceticacid

49 mg (0.09 mmol) of the compound from Example 103 were dissolved in 2ml of methanol, and 193 μl (0.19 mmol) of a 1 N aqueous lithiumhydroxide solution were added. The mixture was stirred at RT for 30 min.The solvent was then removed under reduced pressure, the residue wasdissolved in 5 ml of water and the solution was extracted once with 5 mlof ethyl acetate. The organic phase was discarded. The aqueous phase wasacidified with 0.2 ml of 1 N hydrochloric acid and extracted twice within each case 5 ml of ethyl acetate. The combined organic phases weredried over sodium sulfate, filtered and concentrated under reducedpressure. This gave 40 mg (83% of theory) of the target compound.

LC/MS [Method 4]: R_(t)=0.95 min; MS [ESIpos]: m/z=557 and 559 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.80 (dd, 1H), 3.96 (dd, 1H), 4.26-4.31 (m,1H), 5.03-5.10 (m, 2H), 6.90 (dd, 1H), 6.94 (s, 1H), 7.42-7.51 (m, 3H),7.54-7.58 (m, 1H), 7.59-7.65 (m, 2H), 7.73 (d, 2H), 8.22 (d, 1H).

Example 1052-(2-Chlorophenyl)-2-[4-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1H-1,2,3-triazol-1-yl]acetamide

25 mg (0.045 mmol) of the compound from Example 104 were initiallycharged in 1 ml of DMF, and 9 mg (0.058 mmol) of HOBt and 11 mg (0.058mmol) of EDC were added. After 10 min of stirring at RT, 0.5 ml (0.90mmol) of ammonia solution (35% strength in water) was added, and thereaction was stirred at RT for 16 h. The reaction mixture was thenpurified directly, without any further work-up, by chromatography[Method 19]. This gave 10 mg (40% of theory) of the target compound.

LC/MS [Method 4]: R_(t)=0.99 min; MS [ESIpos]: m/z=556 and 558 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.75-3.85 (m, 1H), 3.91-4.00 (m, 1H),4.23-4.31 (m, 1H), 5.03 (s, 2H), 6.76 (s, 1H), 6.90 (d, 1H), 7.47 (br.s, 3H), 7.55 (m, 1H), 7.59-7.65 (m, 2H), 7.71 (d, 3H), 7.85 (m, 1H),8.08 (br. s, 1H).

Example 1065-(4-Chlorophenyl)-2-({1-[1-(2-chlorophenyl)-2-hydroxyethyl]-1H-1,2,3-triazol-4-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

48 mg (0.084 mmol) of the compound from Example 103 were dissolved in 2ml of THF, and 88 μl (0.088 mmol) of a 1 M solution of lithium aluminumhydride in THF were added at −10° C. After the addition had ended, themixture was stirred at RT for 1 h. For work-up, 2 ml of saturatedaqueous sodium potassium tartrate solution were added at RT, and themixture was extracted with 5 ml of ethyl acetate. The organic phase waswashed once with 5 ml of saturated sodium chloride solution, dried overmagnesium sulfate, filtered and concentrated under reduced pressure. Thecrude product was purified chromatographically [Method 19]. This gave 8mg (18% of theory) of the target compound.

LC/MS [Method 2]: R_(t)=2.20 min; MS [ESIpos]: m/z=543 and 545 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.81 (dd, 1H), 3.93-4.04 (m, 2H), 4.21-4.32(m, 1H), 5.02-5.12 (m, 2H), 5.45 (dd, 1H), 6.14 (dd, 1H), 6.90 (d, 1H),7.32-7.41 (m, 3H), 7.50-7.54 (m, 1H), 7.60-7.65 (m, 2H), 7.71-7.76 (m,2H), 8.34 (s, 1H).

Example 107Ethyl[4-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1H-1,2,3-triazol-1-yl][2-(trifluoromethyl)phenyl]acetate

158 mg (0.15 mmol) of the compound from Example 98A (purity about 30%)were initially charged in 2 ml of acetonitrile, and 9.9 mg (0.15 mmol)of sodium azide were added. The mixture was stirred at RT for 1 h. 0.3mg (0.002 mmol) of copper(II) acetate monohydrate and 63 mg (0.18 mmol)of the compound from Example 14A were then added. The resulting mixturewas stirred at 50° C. for 20 h. The reaction mixture was then filteredthrough a little silica gel, the product being eluted with about 10 mlof ethyl acetate, and the filtrate was concentrated under reducedpressure. The crude product was purified chromatographically [Method19]. This gave 9 mg (8% of theory) of the target compound.

LC/MS [Method 3]: R_(t)=1.36 min; MS [ESIpos]: m/z=619 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=1.13 (t, 3H), 3.81 (dd, 1H), 3.96 (dd, 1H),4.17-4.31 (m, 3H), 5.01-5.11 (m, 2H), 6.89 (dd, 1H), 6.93 (d, 1H),7.59-7.75 (m, 6H), 7.77-7.88 (m, 2H), 8.29 (d, 1H).

Example 1085-(4-Chlorophenyl)-4-cyclopropyl-2-({4-[2-(trifluoromethyl)phenyl]-1H-1,2,3-triazol-1-yl}-methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

60 mg (0.21 mmol) of the compound from Example 122A were dissolved in 2ml of acetonitrile, 14 mg (0.21 mmol) of sodium azide were added and themixture was stirred at RT for 1 h. 0.4 mg (0.002 mmol) of copper(II)acetate monohydrate and 43 mg (0.25 mmol) of1-ethynyl-2-(trifluoro-methyl)benzene were then added. The resultingmixture was stirred at RT for 20 h. For work-up, 10 ml of ethyl acetatewere added and the mixture was washed twice with in each case 5 ml ofwater. The organic phase was dried over sodium sulfate, filtered andconcentrated under reduced pressure. The crude product was purifiedchromatographically [Method 19]. This gave 48 mg (45% of theory) of thetarget compound.

LC/MS [Method 4]: R_(t)=1.15 min; MS [ESIpos]: m/z=461 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=0.57-0.63 (m, 2H), 0.85-0.92 (m, 2H), 3.19(m, 1H), 6.44 (s, 2H), 7.58-7.68 (m, 3H), 7.74-7.84 (m, 4H), 7.87 (d,1H), 8.42 (s, 1H).

Example 1095-(4-Chlorophenyl)-4-cyclopropyl-2-({4-[3-(trifluoromethyl)phenyl]-1H-1,2,3-triazol-1-yl}-methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

Analogously to the preparation of the compound in Example 108, 60 mg(0.21 mmol) of the compound from Example 122A gave 21 mg (21% of theory)of the title compound.

LC/MS [Method 4]: R_(t)=1.19 min; MS [ESIpos]: m/z=461 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=0.59-0.64 (m, 2H), 0.85-0.92 (m, 2H), 3.18(m, 1H), 6.39 (s, 2H), 7.57-7.62 (m, 2H), 7.66-7.73 (m, 2H), 7.78-7.83(m, 2H), 8.19-8.26 (m, 2H), 8.91 (s, 1H).

Example 1105-(4-Chlorophenyl)-2-{[1-(2-chlorophenyl)-1H-imidazol-4-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

19 mg (0.06 mmol) of the compound from Example 5A were dissolved in 5 mlof acetonitrile, and 17 mg (0.13 mmol) of potassium carbonate and 17 mg(0.06 mmol) of the compound from Example 42A were added. The mixture wasstirred at 65° C. for 2 h and then stirred at RT for 20 h. For work-up,5 ml of water were added and the mixture was extracted twice with ineach case 10 ml of ethyl acetate. The organic phase was washed once with5 ml of saturated sodium chloride solution, dried over sodium sulfate,filtered and concentrated under reduced pressure. The crude product waspurified chromatographically [Method 19]. This gave 4 mg (12% of theory)of the target compound.

LC/MS [Method 4]: R_(t)=1.04 min; MS [ESIpos]: m/z=498 and 500 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.83 (dd, 1H), 3.99 (dd, 1H), 4.27-4.37 (m,1H), 4.89-4.96 (m, 2H), 6.92 (br. s, 1H), 7.37 (s, 1H), 7.47-7.57 (m,3H), 7.62 (d, 2H), 7.67-7.72 (m, 1H), 7.76 (d, 2H), 7.87 (s, 1H).

Example 1115-(4-Chlorophenyl)-2-{[1-(2-chlorophenyl)-1H-pyrazol-4-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

27 mg (0.09 mmol) of the compound from Example 5A were dissolved in 2 mlof acetonitrile, and 58 mg (0.18 mmol) of cesium carbonate and 24 mg(0.09 mmol) of the compound from Example 43A were added. The mixture wasstirred at 65° C. for 2 h and then at RT for 20 h. For work-up, 5 ml ofwater were added and the mixture was extracted twice with in each case10 ml of ethyl acetate. The organic phase was washed once with 5 ml ofsaturated sodium chloride solution, dried over sodium sulfate, filteredand concentrated under reduced pressure. The crude product was purifiedchromatographically [Method 19]. This gave 25 mg (56% of theory) of thetarget compound.

LC/MS [Method 4]: R_(t)=1.11 min; MS [ESIpos]: m/z=498 and 500 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.82 (dd, 1H), 3.98 (dd, 1H), 4.31 (d, 1H),4.92-5.01 (m, 2H), 6.90 (d, 1H), 7.45-7.52 (m, 2H), 7.55-7.70 (m, 4H),7.73-7.79 (m, 3H), 8.16 (s, 1H).

Example 1124-Allyl-5-(4-chlorophenyl)-2-{[1-(2,6-dichlorobenzyl)-1H-imidazol-5-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one

41 mg (0.17 mmol) of the compound from Example 12A were dissolved in 2ml of DMF, and 48 mg (0.17 mmol) of the compound from Example 40A and 85mg (0.26 mmol) of cesium carbonate were added. The mixture was stirredat 80° C. for 16 h. After cooling to RT, the reaction mixture wasdiluted with 1 ml of methanol and directly purified chromatographically[Method 19]. This gave 4 mg (5% of theory) of the target compound.

LC/MS [Method 5]: R_(t)=2.01 min; MS [ESIpos]: m/z=474 and 476 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=4.35 (d, 2H), 4.98 (s, 2H), 5.09 (d, 1H),5.23 (d, 1H), 5.29-5.42 (m, 2H), 5.83-5.96 (m, 1H), 7.07 (s, 1H),7.22-7.29 (m, 1H), 7.34-7.43 (m, 4H), 7.50-7.61 (m, 3H).

Example 1134-Allyl-5-(4-chlorophenyl)-2-{[1-(2,6-dichlorobenzyl)-4-nitro-1H-imidazol-2-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one

110 mg (0.47 mmol) of the compound from Example 12A were dissolved in 10ml of DMF, and 150 mg (0.47 mmol) of the compound from Example 41A and229 mg (0.70 mmol) of cesium carbonate were added. The mixture wasstirred at 80° C. for 16 h. After cooling to RT, the reaction mixturewas added to about 25 ml of ice-water and stirred for 10 min. Thisresulted in the formation of a precipitate which was filtered off withsuction and washed with water. The solid was dried under high vacuum.This gave 120 mg (44% of theory) of the target compound of a purity of90%.

LC/MS [Method 3]: R_(t)=1.35 min; MS [ESIpos]: m/z=519 and 521 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=4.31-4.45 (m, 2H), 5.03 (d, 1H), 5.16 (d,1H), 5.32 (s, 2H), 5.63 (s, 2H), 5.80-5.92 (m, 1H), 7.50-7.56 (m, 1H),7.57-7.67 (m, 6H), 7.77 (s, 1H).

Example 1145-(4-Chlorophenyl)-4-cyclopropyl-2-({1-[2-(trifluoromethyl)benzyl]-1H-1,2,4-triazol-5-yl}sulfonyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

37 mg (0.10 mmol) of the compound from Example 93A were dissolved in 3ml of dichloromethane, and 21 μl (0.13 mmol) ofN,N-diisopropylethylamine were added. 30 mg (0.13 mmol) of2-(trifluoromethyl)benzyl bromide dissolved in 1 ml of dichloromethanewere then added, and the mixture was stirred at RT for 48 h. Forwork-up, the mixture was concentrated under reduced pressure and thecrude product was purified chromatographically [Method 19]. This gave 33mg (63% of theory) of the target compound.

LC/MS [Method 5]: R_(t)=2.57 min; MS [ESIpos]: m/z=525 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=0.72-0.78 (m, 2H), 0.97-1.04 (m, 2H), 2.94(tt, 1H), 5.60 (s, 2H), 7.40 (d, 1H), 7.46 (d, 2H), 7.48-7.60 (m, 2H),7.69-7.75 (m, 3H), 8.11 (s, 1H).

Example 1155-(4-Chlorophenyl)-4-cyclopropyl-2-{[1-(2,6-dichlorobenzyl)-1H-1,2,4-triazol-5-yl]sulfonyl}-2,4-dihydro-3H-1,2,4-triazol-3-one

37 mg (0.10 mmol) of the compound from Example 93A were dissolved in 3ml of dichloromethane, and 21 μl (0.13 mmol) ofN,N-diisopropylethylamine were added. 30 mg (0.13 mmol) of2,6-dichlorobenzyl bromide dissolved in 1 ml of dichloromethane werethen added, and the mixture was stirred at RT for 20 h. For work-up, themixture was concentrated under reduced pressure and the crude productwas purified chromatographically [Method 19]. This gave 39 mg (74% oftheory) of the target compound.

LC/MS [Method 2]: R_(t)=2.41 min; MS [ESIpos]: m/z=525 and 527 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=0.73-0.79 (m, 2H), 0.98-1.05 (m, 2H), 2.95(tt, 1H), 5.72 (s, 2H), 7.30-7.36 (m, 1H), 7.37-7.43 (m, 2H), 7.46 (d,2H), 7.72 (d, 2H), 8.10 (s, 1H).

Example 1165-(4-Chlorophenyl)-4-(4-methoxybenzyl)-2-({1-[2-(trifluoromethyl)benzyl]-1H-1,2,4-triazol-5-yl}-sulfonyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

334 mg (0.75 mmol) of the compound from Example 94A were dissolved in 5ml of dichloromethane, and 154 μl (0.93 mmol) ofN,N-diisopropylethylamine were added. 223 mg (0.93 mmol) of2-(trifluoromethyl)benzyl bromide dissolved in 0.5 ml of dichloromethanewere then added, and the mixture was stirred at RT for 20 h. Forwork-up, the mixture was concentrated under reduced pressure and thecrude product was purified chromatographically [Method 19]. This gave245 mg (54% of theory) of the target compound.

LC/MS [Method 3]: R_(t)=1.44 min; MS [ESIpos]: m/z=605 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=3.77 (s, 3H), 4.81 (s, 2H), 5.61 (s, 2H),6.78 (d, 2H), 7.03 (d, 2H), 7.35-7.43 (m, 5H), 7.48-7.58 (m, 2H), 7.74(d, 1H), 8.12 (s, 1H).

Example 1175-(4-Chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2-({1-[2-(trifluoromethyl)benzyl]-1H-1,2,4-triazol-5-yl}sulfonyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

50 mg (0.10 mmol) of the compound from Example 95A together with 50 mg(0.16 mmol) of cesium carbonate were dissolved in 0.5 ml of DMF, and 30mg (0.16 mmol) of 3-bromo-1,1,1-trifluoropropan-2-ol were added. Themixture was then stirred at 75° C. for 8 h. For work-up, the reactionmixture was diluted with 0.5 ml of acetonitrile and directly purifiedchromatographically [Method 19]. This gave 15 mg (22% of theory) of thetarget compound.

LC/MS [Method 5]: R_(t)=2.61 min; MS [ESIpos]: m/z=597 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=3.86 (dd, 1H), 3.95 (dd, 1H), 4.28-4.34 (m,1H), 4.68-4.76 (m, 1H), 5.62 (s, 2H), 7.42 (d, 1H), 7.47 (d, 2H),7.50-7.61 (m, 2H), 7.68 (d, 2H), 7.74 (d, 1H), 8.15 (s, 1H).

Example 1184-Allyl-5-(4-chlorophenyl)-2-{[1-(2,6-dichlorobenzyl)-4-methyl-1H-imidazol-5-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-oneand4-allyl-5-(4-chlorophenyl)-2-{[1-(2,6-dichlorobenzyl)-5-methyl-1H-imidazol-4-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one(regioisomer mixture)

110 mg (0.33 mmol) of the compound from Example 96A together with 88 mg(0.37 mmol) of 2,6-dichlorobenzyl bromide were dissolved in 5 ml of DMF,and 130 mg (0.40 mmol) of cesium carbonate were added. The mixture wasstirred at 60° C. for 6 h. After cooling to RT, the reaction mixture wasdiluted with 1 ml of methanol and directly purified chromatographically[Method 19]. This gave 9 mg (6% of theory) of a mixture of theregioisomeric title compounds in a ratio of about 1:1.

LC/MS [Method 3]: R_(t)=1.08 min; MS [ESIpos]: m/z=488/490 (M+H)⁺ andR_(t)=1.10 min; MS [ESIpos]: m/z=488/490 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=2.38 and 2.42 (2s, 3H), 4.30-4.41 (m, 2H),4.97 and 5.49 (2s, 2H), 5.05-5.32 (m, 4H), 5.84-5.95 (m, 1H), 6.97 and7.13 (2s, 1H), 7.24-7.47 (m, 5H), 7.49-7.58 (m, 2H).

Example 1195-(4-Chlorophenyl)-4-cyclopropyl-2-({4-methyl-1-[3-(trifluoromethyl)benzyl]-1H-imidazol-5-yl}-methyl)-2,4-dihydro-3H-1,2,4-triazol-3-oneand5-(4-Chlorophenyl)-4-cyclopropyl-2-({5-methyl-1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}-methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one(regioisomer mixture)

40 mg (0.12 mmol) of the compound from Example 97A together with 88 mg(0.37 mmol) of 3-(trifluoromethyl)benzyl bromide were dissolved in 3 mlof DMF, and 47 mg (0.15 mmol) of cesium carbonate were added. Themixture was stirred at 60° C. for 3 h. For work-up, after cooling to RT,the mixture was diluted with 5 ml of water and the mixture was extractedthree times with in each case 10 ml of ethyl acetate. The combinedorganic phases were dried over sodium sulfate, filtered and concentratedunder reduced pressure. The residue was taken up in 4 ml of methanol andpurified chromatographically [Method 19]. This gave 20 mg (32% oftheory) of a mixture of the regioisomeric title compounds in a ratio ofabout 1:1.8.

LC/MS [Method 5]: R_(t)=1.75 min; MS [ESIpos]: m/z=488 (M+H)⁺ andR_(t)=1.89 min; MS [ESIpos]: m/z=488 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=0.53-0.59 and 0.70-0.76 (2m, 2H), 0.91-1.03(m, 2H), 2.21 and 2.40 (2s, 3H), 2.80 and 2.94 (2tt, 1H), 4.82 and 4.93(2s, 2H), 5.30 and 5.43 (2s, 2H), 7.11 and 7.19 (2d, 1H), 7.31-7.52 (m,6H), 7.54-7.59 and 7.66-7.70 (2m, 2H).

Example 1205-(4-Chlorophenyl)-4-cyclopropyl-2-[2-(2-methylphenoxy)benzyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

100 mg (0.25 mmol) of the compound from Example 99A, 53 mg (0.49 mmol)of o-cresol and 91 mg (0.74 mmol) of 4-N,N-dimethylaminopyridine weredissolved in 5 ml of acetonitrile, and 39 mg (0.62 mmol) of copperpowder and 49 mg (0.62 mmol) of copper(II) oxide were added. The mixturewas stirred at 85° C. for 16 h. For work-up, the mixture was cooled toRT and filtered through silica gel, and the residue was rinsed with alittle ethyl acetate. The filtrate was concentrated under reducedpressure and the crude product was then purified chromatographically[Method 19]. This gave 25 mg (23% of theory) of the target compound.

LC/MS [Method 4]: R_(t)=1.33 min; MS [ESIpos]: m/z=432 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=0.34-0.44 (m, 2H), 0.76-0.85 (m, 2H), 2.18(s, 3H), 3.05 (tt, 1H), 5.00 (s, 2H), 6.59-6.71 (m, 2H), 7.01 (t, 1H),7.05-7.15 (m, 2H), 7.24-7.32 (m, 2H), 7.35 (d, 1H), 7.56 (d, 2H), 7.71(d, 2H).

Example 1212-[(2′-Chloro-4-fluorobiphenyl-3-yl)methyl]-5-(4-chlorophenyl)-4-cyclopropyl-2,4-dihydro-3H-1,2,4-triazol-3-one

Analogously to the preparation of Example 122, 89 mg (0.15 mmol) of thecompound from Example 100A were reacted with 59 mg (0.23 mmol) of2-chlorophenylboronic acid. This gave 51 mg (73% of theory) of thetarget compound.

LC/MS [Method 4]: R_(t)=1.35 min; MS [ESIpos]: m/z=454 and 456 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=0.54-0.61 (m, 2H), 0.84-0.91 (m, 2H),3.14-3.20 (m, 1H), 5.04 (s, 2H), 7.28-7.36 (m, 1H), 7.37-7.47 (m, 5H),7.53-7.59 (m, 3H), 7.77 (d, 2H).

Example 1222-[(2′-Chlorobiphenyl-3-yl)methyl]-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

72 mg (0.15 mmol) of the compound from Example 101A and 59 mg (0.23mmol) of 2-chlorophenylboronic acid were dissolved in 2 ml of dioxane. Astream of argon was passed through this solution for 10 min, and 8.7 mg(0.008 mmol) of tetrakis(triphenylphosphine)palladium(0) were addedunder argon. The mixture was heated to the boil, and 0.15 ml (0.30 mmol)of a 2 N aqueous sodium carbonate solution was added under argon. Themixture was then stirred under reflux for 20 h. After cooling to RT, themixture was diluted with 10 ml of water and extracted twice with in eachcase 15 ml of ethyl acetate. The combined organic phases were dried overmagnesium sulfate, filtered and concentrated under reduced pressure. Thecrude product was purified chromatographically [Method 19]. This gave 51mg (61% of theory) of the target compound.

LC/MS [Method 4]: R_(t)=1.30 min; MS [ESIpos]: m/z=508 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.83 (dd, 1H), 4.00 (dd, 1H), 4.26-4.34 (m,1H), 5.01-5.13 (m, 2H), 6.88 (d, 1H), 7.32-7.50 (m, 7H), 7.54-7.59 (m,1H), 7.62 (d, 2H), 7.74 (d, 2H).

Example 1235-(4-Chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2-{[2′-(trifluoromethyl)biphenyl-3-yl]-methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one

Analogously to the preparation of Example 122, 72 mg (0.15 mmol) of thecompound from Example 101A were reacted with 43 mg (0.23 mmol) of2-(trifluoromethyl)phenylboronic acid. This gave 49 mg (58% of theory)of the target compound.

LC/MS [Method 4]: R_(t)=1.31 min; MS [ESIpos]: m/z=542 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.84 (dd, 1H), 3.99 (dd, 1H), 4.26-4.32 (m,1H), 4.99-5.12 (m, 2H), 6.88 (d, 1H), 7.22-7.29 (m, 2H), 7.34-7.47 (m,3H), 7.57-7.64 (m, 3H), 7.67-7.76 (m, 3H), 7.83 (d, 1H).

Example 1245-(4-Chlorophenyl)-2-[(2′,3′-dichlorobiphenyl-3-yl)methyl]-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

Analogously to the preparation of Example 122, 94 mg (0.20 mmol) of thecompound from Example 102A were reacted with 56 mg (0.23 mmol) of2,3-dichlorophenylboronic acid. This gave 48 mg (45% of theory) of thetarget compound.

LC/MS [Method 3]: R_(t)=1.54 min; MS [ESIpos]: m/z=542 and 544 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.84 (dd, 1H), 4.00 (dd, 1H), 4.27-4.35 (m,1H), 5.02-5.12 (m, 2H), 6.89 (d, 1H), 7.34-7.42 (m, 4H), 7.42-7.51 (m,2H), 7.60-7.64 (m, 2H), 7.68 (dd, 1H), 7.72-7.77 (m, 2H).

Example 1255-(4-Chlorophenyl)-2-{[5-fluoro-2′-(trifluoromethyl)biphenyl-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

Analogously to the preparation of Example 122, 59 mg (0.12 mmol) of thecompound from Example 103A were reacted with 36 mg (0.18 mmol) of2-(trifluoromethyl)phenylboronic acid. This gave 43 mg (64% of theory)of the target compound.

LC/MS [Method 4]: R_(t)=1.34 min; MS [ESIpos]: m/z=560 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.84 (dd, 1H), 3.99 (dd, 1H), 4.26-4.33 (m,1H), 5.03-5.14 (m, 2H), 6.89 (d, 1H), 7.10-7.23 (m, 3H), 7.43 (d, 1H),7.59-7.68 (m, 3H), 7.70-7.77 (m, 3H), 7.85 (d, 1H).

Example 1262-[(2′-Chloro-5-fluorobiphenyl-3-yl)methyl]-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

Analogously to the preparation of Example 122, 59 mg (0.12 mmol) of thecompound from Example 103A were reacted with 28 mg (0.18 mmol) of2-chlorophenylboronic acid. This gave 34 mg (54% of theory) of thetarget compound.

LC/MS [Method 4]: R_(t)=1.34 min; MS [ESIpos]: m/z=526 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.84 (dd, 1H), 4.00 (dd, 1H), 4.26-4.34 (m,1H), 5.04-5.15 (m, 2H), 6.90 (d, 1H), 7.16-7.21 (m, 1H), 7.22-7.28 (m,2H), 7.40-7.47 (m, 3H), 7.55-7.65 (m, 3H), 7.75 (d, 2H).

Example 1272-[(5-Bromo-2′-chlorobiphenyl-3-yl)methyl]-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

Analogously to the preparation of Example 91, 109 mg (0.36 mmol) of thecompound from Example 5A were reacted with 128 mg (0.36 mmol) of thecompound from Example 117A. This gave 148 mg (68% of theory) of thetarget compound.

LC/MS [Method 4]: R_(t)=1.40 min; MS [ESIpos]: m/z=586, 588 and 590(M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.83 (dd, 1H), 3.97-4.03 (m, 1H), 4.26-4.34(m, 1H), 5.03-5.13 (m, 2H), 6.88 (d, 1H), 7.40-7.47 (m, 4H), 7.55-7.60(m, 3H), 7.61-7.65 (m, 2H), 7.71-7.77 (m, 2H).

Example 1285-(4-Chlorophenyl)-2-[(2,2″-dichloro-1,1′:3′,1″-terphenyl-5′-yl)methyl]-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

Analogously to the preparation of Example 91, 105 mg (0.34 mmol) of thecompound from Example 5A were reacted with 135 mg (0.35 mmol) of thecompound from Example 118A. This gave 115 mg (53% of theory) of thetarget compound.

LC/MS [Method 4]: R_(t)=1.47 min; MS [ESIpos]: m/z=618 and 620 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.83 (dd, 1H), 4.00 (dd, 1H), 4.26-4.32 (m,1H), 5.08-5.20 (m, 2H), 6.86 (d, 1H), 7.39-7.52 (m, 9H), 7.55-7.65 (m,4H), 7.74 (d, 2H).

Example 129 Methyl2′-chloro-3-{[3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]methyl}biphenyl-4-carboxylate

Analogously to the preparation of Example 122, 265 mg (0.50 mmol) of thecompound from Example 104A were reacted with 194 mg (0.74 mmol) of2-chlorophenylboronic acid. This gave 54 mg (19% of theory) of thetarget compound of a purity of 98% and 167 mg (49% of theory) of apurity of 83%.

LC/MS [Method 3]: R_(t)=1.49 min; MS [ESIpos]: m/z=566 and 568 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.84 (dd, 1H), 3.90 (s, 3H), 3.99 (dd, 1H),4.24-4.32 (m, 1H), 5.36-5.47 (m, 2H), 6.85 (d, 1H), 7.33 (d, 1H),7.38-7.47 (m, 3H), 7.51-7.59 (m, 2H), 7.62 (d, 2H), 7.72 (d, 2H), 8.00(d, 1H).

Example 130 Methyl3-{[3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]methyl}-2′-(trifluoromethyl)biphenyl-4-carboxylate

Analogously to the preparation of Example 122, 265 mg (0.50 mmol) of thecompound from Example 104A were reacted with 149 mg (0.74 mmol) of2-(trifluoromethyl)phenylboronic acid. This gave 113 mg (38% of theory)of the target compound of a purity of 100% and 101 mg (28% of theory) ofa purity of 81%.

LC/MS [Method 3]: R_(t)=1.50 min; MS [ESIpos]: m/z=600 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.83 (dd, 1H), 3.90 (s, 3H), 3.97 (dd, 1H),4.19-4.30 (m, 1H), 5.34-5.47 (m, 2H), 6.83 (d, 1H), 7.16 (s, 1H),7.37-7.45 (m, 2H), 7.59-7.77 (m, 6H), 7.83 (d, 1H), 7.98 (d, 1H).

Example 131 Methyl2′,3′-dichloro-3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)biphenyl-4-carboxylate

Analogously to the preparation of Example 75, 455 mg (0.85 mmol) of thecompound from Example 105A were reacted with 244 mg (1.28 mmol) of2,3-dichlorophenylboronic acid. This gave 347 mg (57% of theory) of thetarget compound.

LC/MS [Method 4]: R_(t)=1.38 min; MS [ESIpos]: m/z=600 and 602 (M+H)⁺.

Example 1322′-Chloro-3-{[3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]methyl}biphenyl-4-carboxylicacid

204 mg (0.36 mmol) of the compound from Example 129 were dissolved in 3ml of THF, and 0.4 ml of a 1 N aqueous lithium hydroxide solution wasadded. The mixture was stirred at RT for 20 h. For work-up, the solventwas removed under reduced pressure, the residue was taken up in about 5ml of water and 0.07 ml of 6 N hydrochloric acid was added. Theprecipitated solid was filtered off with suction and dried. Furtherpurification of the crude product was carried out by chromatography onsilica gel (mobile phase: first cyclohexane/ethyl acetate 1:3, then pureethyl acetate, finally dichloromethane/methanol 1:1). This gave 97 mg(47% of theory) of the target compound.

LC/MS [Method 4]: R_(t)=1.20 min; MS [ESIpos]: m/z=552 and 554 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.80 (dd, 1H), 3.99 (dd, 1H), 4.33-4.43 (m,1H), 5.33-5.44 (m, 1H), 5.49-5.58 (m, 1H), 7.10 (s, 1H), 7.28-7.43 (m,4H), 7.50-7.55 (m, 1H), 7.60 (d, 2H), 7.71 (d, 2H), 7.74-7.83 (m, 1H).

Example 1333-{[3-(4-Chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]methyl}-2′-(trifluoromethyl)biphenyl-4-carboxylicacid

195 mg (0.36 mmol) of the compound from Example 130 were dissolved in 3ml of THF, and 0.4 ml a 1 N aqueous lithium hydroxide solution wereadded. The mixture was stirred at RT for 20 h. For work-up, the solventwas removed under reduced pressure, the residue was taken up in about 5ml of water and 0.07 ml of 6 N hydrochloric acid was added. The mixturewas stirred for 15 min, and the precipitated solid was then filtered offwith suction and dried under high vacuum. This gave 146 mg (73% oftheory) of the target compound.

LC/MS [Method 3]: R_(t)=1.38 min; MS [ESIpos]: m/z=586 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.78 (dd, 1H), 3.95 (dd, 1H), 4.31-4.39 (m,1H), 5.25-5.34 (m, 1H), 5.40-5.47 (m, 1H), 7.02 (s, 1H), 7.24 (d, 1H),7.37 (d, 1H), 7.56-7.63 (m, 2H), 7.66-7.83 (m, 6H).

Example 1342′,3′-Dichloro-3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)biphenyl-4-carboxylicacid

347 mg (0.49 mmol) of the compound from Example 131 (purity 84%) werereacted analogously to the preparation of Example 132. This gave 243 mg(85% of theory) of the target compound.

LC/MS [Method 4]: R_(t)=1.24 min; MS [ESIpos]: m/z=586 and 588 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.84 (dd, 1H), 3.99 (dd, 1H), 4.23-4.31 (m,1H), 5.40-5.51 (m, 2H), 6.88 (br. s, 1H), 7.24 (s, 1H), 7.33-7.37 (m,1H), 7.45 (t, 1H), 7.50 (d, 1H), 7.62 (d, 2H), 7.69 (dd, 1H), 7.73 (d,2H), 8.01 (d, 1H).

Example 1352′-Chloro-3-{[3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]methyl}biphenyl-4-carboxamide

43 mg (0.08 mmol) of the compound from Example 132 were initiallycharged in 1 ml of DMF, and 14 mg (0.10 mmol) of HOBt and 19 mg (0.10mmol) of EDC were added. After 10 min of stirring at RT, 0.41 ml (0.20mmol) of ammonia solution (35% strength in water) was added, and themixture was stirred at RT for 16 h. Under reduced pressure, the reactionsolution was then freed of excess ammonia, about 3 ml of water wereadded and the mixture was extracted three times with in each case 5 mlof ethyl acetate. The combined organic phases were dried over magnesiumsulfate, filtered and concentrated under reduced pressure. The crudeproduct was purified chromatographically on silica gel (mobile phase:cyclohexane/ethyl acetate 1:3→1:5). This gave 19 mg (42% of theory) ofthe target compound.

LC/MS [Method 4]: R_(t)=1.14 min; MS [ESIpos]: m/z=551 and 553 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.83 (dd, 1H), 3.98 (dd, 1H), 4.24-4.33 (m,1H), 5.22-5.34 (m, 2H), 6.84 (d, 1H), 7.27 (s, 1H), 7.34-7.47 (m, 4H),7.52-7.66 (m, 3H), 7.73 (d, 2H), 8.04 (s, 1H).

Example 1362′,3′-Dichloro-3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)biphenyl-4-carboxamide

45 mg (0.07 mmol) of the compound from Example 134 were initiallycharged in 1 ml of DMF, and 13 mg (0.09 mmol) of HOBt and 18 mg (0.09mmol) of EDC were added. After 10 min of stirring at RT, 80 μl (1.44mmol) of ammonia solution (35% strength in water) were added, and themixture was stirred at RT for 16 h. Under reduced pressure, the reactionsolution was then freed of excess ammonia, about 3 ml of water wereadded and the mixture was extracted three times with in each case 5 mlof ethyl acetate. The combined organic phases were dried over magnesiumsulfate, filtered and concentrated under reduced pressure. The crudeproduct was purified chromatographically [Method 19]. This gave 20 mg(46% of theory) of the target compound.

LC/MS [Method 3]: R_(t)=1.36 min; MS [ESIpos]: m/z=585 and 587 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.83 (dd, 1H), 3.98 (dd, 1H), 4.23-4.32 (m,1H), 5.22-5.33 (m, 2H), 6.84 (d, 1H), 7.24 (s, 1H), 7.30-7.35 (m, 1H),7.41-7.47 (m, 2H), 7.56-7.65 (m, 4H), 7.65-7.70 (m, 1H), 7.73 (d, 2H),8.06 (s, 1H).

Example 1375-(4-Chlorophenyl)-2-{[2′,3′-dichloro-4-(hydroxymethyl)biphenyl-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

230 mg (0.39 mmol) of the compound from Example 134 were dissolved in 5ml of THF, the solution was cooled to 0° C. and 55 μl (0.39 mmol) oftriethylamine and also 56 μl (0.43 mmol) of isobutyl chloroformate wereadded. The mixture was stirred at 0° C. for 1 h. The suspension was thenfiltered through a Seitz frit into a flask cooled to 0° C., and theresidue was rinsed with about 2 ml of THF. With vigorous stirring, thissolution was added to a solution, cooled to 0° C., of 44 mg (1.18 mmol)of sodium borohydride in 0.6 ml of water. After 1 h, 5 ml of saturatedaqueous sodium bicarbonate solution were added, and the mixture waswarmed to RT. The mixture was extracted with 15 ml of ethyl acetate. Theorganic phase was washed successively with in each case 5 ml ofsaturated sodium bicarbonate solution and saturated sodium chloridesolution. After drying over sodium sulfate, the mixture was filtered andconcentrated under reduced pressure. The crude product was purifiedchromatographically [Method 19]. This gave 13 mg (6% of theory) of thetarget compound.

LC/MS [Method 3]: R_(t)=1.44 min; MS [ESIneg]: m/z=572 (M−H)⁻

¹H-NMR (400 MHz, DMSO-d₆): δ=3.82 (dd, 1H), 3.98 (dd, 1H), 4.23-4.30 (m,1H), 4.74 (d, 2H), 5.05-5.15 (m, 2H), 5.30 (t, 1H), 6.86 (d, 1H), 7.27(d, 1H), 7.33 (dd, 1H), 7.38 (dd, 1H), 7.43 (t, 1H), 7.54 (d, 1H), 7.61(d, 2H), 7.66 (dd, 1H), 7.70-7.74 (m, 2H).

Example 138[2′,3′-Dichloro-3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)biphenyl-4-yl]methylcarbamate

65 mg (0.11 mmol) of the compound from Example 137 were dissolved in 3ml of dichloromethane, and the mixture was cooled to 0° C. 14 μl (0.16mmol) of chlorosulfonyl isocyanate were added, and the mixture wasstirred at RT for 18 h. 1.5 ml of water were then added, and the mixturewas stirred at 60° C. for a further 18 h. For work-up, 3 ml of saturatedaqueous sodium bicarbonate solution were added, and the mixture wasextracted twice with in each case 10 ml of ethyl acetate. The combinedorganic phases were dried over sodium sulfate, filtered and concentratedunder reduced pressure. The crude product was purifiedchromatographically [Method 19]. This gave 30 mg (43% of theory) of thetarget compound.

LC/MS [Method 4]: R_(t)=1.23 min; MS [ESIneg]: m/z=615 and 617 (M−H)⁻

¹H-NMR (400 MHz, DMSO-d₆): δ=3.82 (dd, 1H), 3.98 (dd, 1H), 4.26-4.33 (m,1H), 5.08-5.18 (m, 2H), 5.23 (s, 2H), 6.66 (br. s, 2H), 6.86 (d, 1H),7.32 (d, 1H), 7.34 (dd, 1H), 7.39-7.51 (m, 3H), 7.59-7.64 (m, 2H), 7.67(dd, 1H), 7.73 (d, 2H).

Example 139 Methyl5-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-2′-(trifluoromethyl)biphenyl-2-carboxylate

179 mg (0.58 mmol) of the compound from Example 5A and 285 mg (0.88mmol) of cesium carbonate were suspended in 5 ml of acetonitrile, and340 mg (0.58 mmol) of the compound from Example 108A were added. Themixture was stirred under reflux for 4 h. The precipitated solid wasthen filtered off and the filtrate was concentrated under reducedpressure to a volume of about 1.5 ml. After addition of 0.5 ml of 1 Nhydrochloric acid, the mixture was directly purified chromatographically[Method 19]. This gave 231 mg (65% of theory) of the target compound.

LC/MS [Method 4]: R_(t)=1.26 min; MS [ESIpos]: m/z=600 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.52 (s, 3H), 3.84 (dd, 1H), 3.99 (dd, 1H),4.25-4.32 (m, 1H), 5.03-5.18 (m, 2H), 6.88 (dd, 1H), 7.21-7.29 (m, 2H),7.46 (d, 1H), 7.55-7.69 (m, 4H), 7.70-7.75 (m, 2H), 7.77 (d, 1H), 7.97(d, 1H).

Example 140 Methyl2′-chloro-5-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)biphenyl-2-carboxylate

Analogously to the preparation of Example 139, 208 mg (0.68 mmol) of thecompound from Example 5A were reacted with 230 mg (0.68 mmol) of thecompound from Example 109A. This gave 231 mg (59% of theory) of thetarget compound.

LC/MS [Method 4]: R_(t)=1.26 min; MS [ESIpos]: m/z=566 and 568 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.58 (s, 3H), 3.84 (dd, 1H), 4.02 (dd, 1H),4.26-4.33 (m, 1H), 5.07-5.18 (m, 2H), 6.88 (d, 1H), 7.25-7.31 (m, 2H),7.36-7.52 (m, 4H), 7.62 (d, 2H), 7.74 (d, 2H), 7.93 (d, 1H).

Example 1415-({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-2′-(trifluoromethyl)biphenyl-2-carboxylicacid

215 mg (0.36 mmol) of the compound from Example 139 were dissolved in 3ml of THF and 3 ml of methanol, and 0.36 ml of 2 N aqueous sodiumhydroxide solution was added. The mixture was stirred at 80° C. for 16h. For work-up, the mixture was diluted with 10 ml of water andextracted twice with in each case 10 ml of ethyl acetate. The aqueousphase was acidified with 1 N hydrochloric acid and once more extractedwith 10 ml of ethyl acetate. The organic phases were combined, driedover magnesium sulfate, filtered and concentrated under reducedpressure. The residue was dried under high vacuum. This gave 222 mg(quant.) of the target compound.

LC/MS [Method 3]: R_(t)=1.29 min; MS [ESIpos]: m/z=586 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.84 (dd, 1H), 3.98 (dd, 1H), 4.24-4.31 (m,1H), 5.02-5.16 (m, 2H), 6.88 (dd, 1H), 7.19 (br. s, 1H), 7.26 (d, 1H),7.43 (d, 1H), 7.56 (t, 1H), 7.59-7.67 (m, 3H), 7.69-7.77 (m, 3H), 7.96(d, 1H), 12.59 (br. s, 1H).

Example 1422′-Chloro-5-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)biphenyl-2-carboxylicacid

Analogously to the preparation of Example 141, 218 mg (0.39 mmol) of thecompound from Example 140 were reacted with 2 N aqueous sodium hydroxidesolution. This gave 220 mg (quant.) of the target compound.

LC/MS [Method 3]: R_(t)=1.26 min; MS [ESIpos]: m/z=552 and 554 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.84 (dd, 1H), 4.00 (dd, 1H), 4.24-4.35 (m,1H), 5.05-5.16 (m, 2H), 6.89 (d, 1H), 7.24 (s, 1H), 7.25-7.30 (m, 1H),7.34-7.39 (m, 2H), 7.42 (dd, 1H), 7.45-7.50 (m, 1H), 7.59-7.65 (m, 2H),7.72-7.77 (m, 2H), 7.92 (d, 1H), 12.64 (br. s, 1H).

Example 1435-({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-2′-(trifluoromethyl)biphenyl-2-carboxamide

208 mg (0.36 mmol) of the compound from Example 141 were initiallycharged in 5 ml of DMF, and 62 mg (0.46 mmol) of HOBt and 88 mg (0.46mmol) of EDC were added. After 10 min of stirring at RT, 1.0 ml (16mmol) of ammonia solution (33% strength in water) were added, and themixture was stirred at RT for 16 h. Under reduced pressure, the reactionsolution was then freed from excess ammonia, about 3 ml of water wereadded and the mixture was extracted three times with in each case 5 mlof ethyl acetate. The combined organic phases were dried over magnesiumsulfate, filtered and concentrated under reduced pressure. The crudeproduct was purified chromatographically [Method 19]. This gave 85 mg(39% of theory) of the target compound.

LC/MS [Method 2]: R_(t)=2.29 min; MS [ESIpos]: m/z=585 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.83 (dd, 1H), 3.99 (dd, 1H), 4.24-4.31 (m,1H), 4.98-5.12 (m, 2H), 6.87 (d, 1H), 7.08-7.18 (m, 2H), 7.29 (d, 1H),7.37 (d, 1H), 7.50-7.65 (m, 6H), 7.67-7.76 (m, 3H).

Example 1442′-Chloro-5-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)biphenyl-2-carboxamide

Analogously to the preparation of Example 143, 210 mg (0.38 mmol) of thecompound from Example 142 were reacted with ammonia solution. This gave122 mg (54% of theory) of the target compound.

LC/MS [Method 4]: R_(t)=1.06 min; MS [ESIpos]: m/z=551 and 553 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.84 (dd, 1H), 4.00 (dd, 1H), 4.24-4.35 (m,1H), 5.01-5.12 (m, 2H), 6.88 (d, 1H), 7.17 (s, 1H), 7.23 (d, 1H),7.26-7.31 (m, 1H), 7.31-7.39 (m, 3H), 7.44-7.49 (m, 1H), 7.52-7.59 (m,2H), 7.62 (d, 2H), 7.74 (d, 2H).

Example 145N-tert-Butyl-5-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-2′-(trifluoromethyl)biphenyl-2-carboxamide

30 mg (0.05 mmol) of the compound from Example 141 were initiallycharged in 0.75 ml of DMF, and 9 mg (0.074 mmol) of HOBt and 13 mg (0.07mmol) of EDC were added. After 10 min of stirring at RT, 6 μl (0.06mmol) of 2-methylpropane-2-amine were added, and the mixture was stirredat RT for 16 h. 50 μl of 1 N hydrochloric acid were then added, and themixture was directly purified chromatographically [Method 19]. This gave8.2 mg (24% of theory) of the target compound.

LC/MS [Method 2]: R_(t)=2.70 min; MS [ESIpos]: m/z=641 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=1.08 (s, 9H), 3.84 (dd, 1H), 3.99 (dd, 1H),4.24-4.35 (m, 1H), 4.99-5.11 (m, 2H), 6.88 (d, 1H), 7.17 (d, 1H), 7.25(s, 1H), 7.38 (t, 2H), 7.48 (d, 1H), 7.54-7.67 (m, 4H), 7.71 (d, 2H),7.78 (d, 1H).

Example 146 Methyl2′-chloro-5-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)biphenyl-3-carboxylate

Analogously to the preparation of Example 139, 248 mg (0.81 mmol) of thecompound from Example 5A were reacted with 274 mg (0.81 mmol) of thecompound from Example 112A. This gave 271 mg (59% of theory) of thetarget compound.

LC/MS [Method 3]: R_(t)=1.48 min; MS [ESIpos]: m/z=566 and 568 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.84 (dd, 1H), 3.87 (s, 3H), 4.01 (dd, 1H),4.23-4.33 (m, 1H), 5.10-5.21 (m, 2H), 6.87 (s, 1H), 7.42-7.48 (m, 3H),7.58-7.65 (m, 3H), 7.68-7.76 (m, 3H), 7.93 (s, 1H), 7.99 (s, 1H).

Example 1472′-Chloro-5-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)biphenyl-3-carboxylicacid

Analogously to the preparation of Example 141, 244 mg (0.43 mmol) of thecompound from Example 146 were reacted with 2 N aqueous sodium hydroxidesolution. This gave 242 mg (100% of theory) of the target compound.

LC/MS [Method 3]: R_(t)=1.33 min; MS [ESIpos]: m/z=552 and 554 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.83 (dd, 1H), 3.98-4.04 (m, 1H), 4.29-4.35(m, 1H), 5.04-5.14 (m, 2H), 7.36-7.48 (m, 5H), 7.57 (d, 1H), 7.61 (d,2H), 7.74 (d, 2H), 7.87 (br. s, 1H).

Example 1482′-Chloro-5-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)biphenyl-3-carboxamide

Analogously to the preparation of Example 143, 55 mg (0.10 mmol) of thecompound from Example 147 were reacted with ammonia solution. This gave25 mg (43% of theory) of the target compound.

LC/MS [Method 4]: R_(t)=1.12 min; MS [ESIpos]: m/z=551 and 553 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.83 (dd, 1H), 3.96-4.03 (m, 1H), 4.26-4.33(m, 1H), 5.05-5.16 (m, 2H), 6.52 (s, 1H), 6.89 (d, 1H), 7.41-7.49 (m,4H), 7.55-7.65 (m, 3H), 7.74 (d, 2H), 7.88 (d, 2H), 8.06 (s, 1H).

B. Evaluation of the Pharmacological Activity

The pharmacological action of the compounds according to the inventioncan be shown in the following assays:

ABBREVIATIONS

-   EDTA ethylenediaminetetraacetic acid-   DMEM Dulbecco's Modified Eagle Medium-   FCS fetal calf serum-   HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid-   SmGM Smooth Muscle Cell Growth Media-   Tris-HCl 2-amino-2-(hydroxymethyl)-1,3-propanediol hydrochloride

B-1. Cellular In Vitro Assay for Determining the Vasopressin ReceptorActivity

The identification of agonists and antagonists of the V1a and V2vasopressin receptors from humans and rats and also the quantificationof the activity of the compounds of the invention takes place usingrecombinant cell lines. These cells derive originally from a hamster'sovary epithelial cell (Chinese Hamster Ovary, CHO K1, ATCC: AmericanType Culture Collection, Manassas, Va. 20108, USA). The test cell linesconstitutively express a modified form of the calcium-sensitivephotoprotein aequorin, which, after reconstitution with the cofactorcoelenterazine, emits light when there are increases in the free calciumconcentrations [Rizzuto R, Simpson A W, Brini M, Pozzan T, Nature 358,325-327 (1992)]. In addition, the cells are stably transfected with thehuman or rat V1a or V2 receptors. In the case of the Gs-coupling V2receptors, the cells are stably transfected with a further gene, whichcodes for the promiscuous G_(α16) protein [Amatruda T T, Steele D A,Slepak V Z, Simon M I, Proceedings in the National Academy of ScienceUSA 88, 5587-5591 (1991)], either independently or as a fusion gene. Theresulting vasopressin receptor test cells react to stimulation of therecombinantly expressed vasopressin receptors by intracellular releaseof calcium ions, which can be quantified by the resulting aequorinluminescence using a suitable luminometer [Milligan G, Marshall F, ReesS, Trends in Pharmacological Sciences 17, 235-237 (1996)].

Test Procedure:

On the day before the assay, the cells are plated out in culture medium(DMEM, 10% FCS, 2 mM glutamine, 10 mM HEPES) in 384-well microtiterplates and kept in a cell incubator (96% humidity, 5% v/v CO₂, 37° C.).On the day of the assay, the culture medium is replaced by a Tyrodesolution (140 mM NaCl, 5 mM KCl, 1 mM MgCl₂, 2 mM CaCl₂, 20 mM glucose,20 mM HEPES), which additionally contains the cofactor coelenterazine(50 μM), and the microtiter plate is then incubated for a further 3-4hours. The test substances in various concentrations are placed for 10to 20 minutes in the wells of the microtiter plate before the agonist[Arg⁸]-vasopressin is added, and the resulting light signal is measuredimmediately in the luminometer. The IC₅₀ values are calculated using theGraphPad PRISM computer program (Version 3.02).

The table below lists representative IC₅₀ values for the compounds ofthe invention on the cell line transfected with the human V1a or V2receptor:

TABLE Example No. IC₅₀ hV1a [μM] IC₅₀ hV2 [μM] 9 0.060 0.023 17 0.120.032 20 0.046 0.15 26 0.023 0.028 32 0.0086 0.0020 42 0.0040 0.011 490.019 0.0015 50 0.034 0.0014 54 0.0068 0.0085 60 0.050 0.012 68 0.0120.0083 71 0.0042 0.013 74 0.26 0.040 76 0.017 0.023 78 0.029 0.023 830.23 0.067 84 9.2 1.1 85 9.3 1.7 87 0.26 0.012 90 0.088 0.40 93 0.0890.10 96 0.12 0.0084 101 0.027 0.0044 110 0.0065 0.0033 111 0.031 0.0077112 0.82 0.11 117 0.039 0.045 122 0.57 0.027 132 1.7 0.0046 135 0.490.0058

B-2. Cellular In Vitro Assay for Detecting the Action of Vasopressin V1aReceptor Antagonists on the Regulation of Pro-Fibrotic Genes

The cell line H9C2 described as a cardiomyocyte type (American TypeCulture Collection ATCC No. CRL-1446), isolated from rat cardiac tissue,endogenously expresses the vasopressin V1A receptor AVPR1A in high copynumber, whereas the AVPR2 expression cannot be detected. For cell assaysfor the inhibition of the AVPR1A receptor-dependent regulation of geneexpression by receptor antagonists, the procedure is as follows:

H9C2 cells are seeded in 12-well microtiter plates for cell culture, ata cell density of 100 000 cells/well, in 1.0 ml of Opti-MEM medium(Invitrogen Corp., Carlsbad Calif., USA, Cat. No. 11058-021) with 2% FCSand 1% penicillin/streptomycin solution (Invitrogen, Cat. No.10378-016), and held in a cell incubator (96% humidity, 5% v/v carbondioxide, 37° C.). After 24 hours, sets of three wells (triplicate) arecharged with vehicle solution (negative control), vasopressin solution([Arg⁸]-vasopressin acetate, Sigma, Cat. No. V9879) or test substances(dissolved in vehicle: water with 20% by volume ethanol) and vasopressinsolution. In the cell culture, the final vasopressin concentration is0.05 μM. The test substance solution is added to the cell culture insmall volumes, and so a final concentration of 0.1% of ethanol in thecell assay is not exceeded. After an incubation time of 6 hours, theculture supernatant is drawn off under suction, the adherent cells arelysed in 250 μl of RLT buffer (Qiagen, Ratingen, Cat. No. 79216), andthe RNA is isolated from this lysate using the RNeasy kit (Qiagen, Cat.No. 74104). This is followed by DNAse digestion (Invitrogen, Cat. No.18068-015), cDNA synthesis (Promaga, ImProm-II Reverse TranscriptionSystem, Cat. No. A3800) and RTPCR (pPCR MasterMix RT-QP2X-03-075 fromEurogentec, Seraing, Belgium). All procedures take place in accordancewith the working protocols of the test reagents' manufacturers. Theprimer sets for the RTPCR are selected on the basis of the mRNA genesequences (NCBI Genbank Entrez Nucleotide Data Base) using thePrimer3Plus program with 6-FAM TAMRA-labelled probes. The RTPCR fordetermining the relative mRNA expression in the cells of the variousassay batches is carried out using the Applied Biosystems ABI Prism 7700Sequence Detector in 96-well or 384-well microtiter plate format inaccordance with the instrument operating instructions. The relative geneexpression is represented by the delta-delta Ct value [AppliedBiosystems, User Bulletin No. 2 ABI Prism 7700 SDS Dec. 11, 1997(updated October 2001)] with reference to the level of expression of theribosomal protein L-32 gene (Genbank Acc. No. NM_(—)013226) and thethreshold Ct value of Ct=35.

B-3. In Vivo Assay for Detecting the Cardiovascular Effect: BloodPressure Measurement on Anesthetized Rats (Vasopressin ‘Challenge’Model)

In male Sprague-Dawley rats (250-350 g body weight) underketamine/xylazine/pentobarbital injection anaesthesia, polyethylenetubes (PE-50; Intramedic®), which are prefilled with heparin-containing(500 IU/ml) isotonic sodium chloride solution, are introduced into thejugular vein and the femoral vein and then tied in. Via one venousaccess, with the aid of a syringe, Arg-vasopressin is injected; the testsubstances are administered via the second venous access. Fordetermination of the systolic blood pressure, a pressure catheter(Millar SPR-320 2F) is tied into the carotid artery. The arterialcatheter is connected to a pressure transducer which feeds its signalsto a recording computer equipped with suitable recording software. In atypical experiment the experimental animal is administered 3-4successive bolus injections at intervals of 10-15 min with a definedamount of Arg-vasopressin (30 ng/kg) in isotonic sodium chloridesolution and, when the blood pressure has reached initial levels again,the substance under test is administered as a bolus, with subsequentongoing infusion, in a suitable solvent. After this, at definedintervals (10-15 min), the same amount of Arg-vasopressin as at thestart is administered again. On the basis of the blood pressure values,a determination is made of the extent to which the test substancecounteracts the hypertensive effect of the Arg-vasopressin. Controlanimals receive only solvent instead of the test substance.

Following intravenous administration, the compounds of the invention, incomparison to the solvent controls, bring about an inhibition in theblood pressure increase caused by Arg-vasopressin.

B-4. In Vivo Assay for Detecting the Cardiovascular Effect: DiuresisInvestigations on Conscious Rats in Metabolism Cages

Wistar rats (220-450 g body weight) are kept with free access to feed(Altromin) and drinking water. During the experiment, the animals arekept with free access to drinking water for 4 to 8 hours individually inmetabolism cages suitable for rats of this weight class (TecniplastDeutschland GmbH, D-82383 Hohenpeiβenberg). At the beginning of theexperiment, the animals are administered the substance under test in avolume of 1 to 3 ml/kg body weight of a suitable solvent by means ofgavage into the stomach. Control animals receive only solvent. Controlsand substance tests are carried out in parallel on the same day. Controlgroups and substance-dose groups each consist of 4 to 8 animals. Duringthe experiment, the urine excreted by the animals is collectedcontinuously in a receiver at the base of the cage. The volume of urineper unit time is determined separately for each animal, and theconcentration of the sodium and potassium ions excreted in the urine ismeasured by standard methods of flame photometry. To obtain a sufficientvolume of urine, the animals are given a defined amount of water bygavage at the beginning of the experiment (typically 10 ml per kilogramof body weight). Before the beginning of the experiment and after theend of the experiment, the body weight of the individual animals isdetermined.

Following oral administration, in comparison with solvent controlapplications, the compounds of the invention bring about an increasedexcretion of urine, which is based essentially on an increased excretionof water (aquaresis).

B-5. In Vivo Assay for Detecting the Cardiovascular Effect: HemodynamicInvestigations on Anesthetized Dogs

Male or female mongrel dogs (Mongrels, Marshall BioResources, USA) witha weight of between 20 and 30 kg are anesthetized with pentobarbital (30mg/kg iv, Narcoren®, Merial, Germany) for the surgical interventions andthe hemodynamic and functional investigation termini. Alcuroniumchloride (Alloferin®, ICN Pharmaceuticals, Germany, 3 mg/animal iv)serves additionally as a muscle relaxant. The dogs are intubated andventilated with an oxygen/ambient air mixture (40/60%), about 5-6 L/min)Ventilation takes place using a ventilator from Draeger (Sulla 808) andis monitored using a carbon dioxide analyzer (Engstrom). The anesthesiais maintained by continual infusion of pentobarbital (50 μg/kg/min);fentanyl is used as an analgesic (10 μg/kg/h). One alternative topentobarbital is to use isoflurane (1-2% by volume).

In preparatory interventions, the dogs are fitted with a cardiacpacemaker. At a time of 21 days before the first drug testing (i.e.start of experiment), a cardiac pacemaker from Biotronik (Logos®) isimplanted into a subcutaneous skin pocket and is contacted with theheart via a pacemaker electrode which is advanced through the externaljugular vein, with illumination, into the right ventricle.

At the same time as the implanting of the pacemaker, through retrogradeadvancing of 7F biopsy forceps (Cordis) via a sheath introducer(Avanti+®; Cordis) in the fermoral artery, and after atraumatic passagethrough the aortic valve, there is defined lesion of the mitral valve,with monitoring by echo cardiography and illumination. Thereafter all ofthe accesses are removed and the dog wakes spontaneously from theanesthesia. After a further 7 days (i.e. 14 days before the first drugtesting), the above-described pacemaker is activated and the heart isstimulated at a frequency of 220 beats per minute.

The actual drug testing experiments take place 14 and 28 days after thebeginning of pacemaker stimulation, using the following instrumentation:

-   -   Introduction of a bladder catheter for bladder relief and for        measuring the flow of urine    -   Attachment of ECG leads to the extremities for ECG measurement    -   Introduction of a Fluidmedic PE-300 tube filled with sodium        chloride solution into the femoral artery. This tube is        connected to a pressure sensor (Braun Melsungen, Melsungen,        Germany) for measuring the systemic blood pressure    -   Introduction of a Millar Tip catheter (type 350 PC, Millar        Instruments, Houston, USA) through the left atrium or through a        port secured in the carotid artery, for measuring cardiac        hemodynamics    -   Introduction of a Swan-Ganz catheter (CCOmbo 7.5F, Edwards,        Irvine, USA) via the jugular vein into the pulmonary artery, for        measuring the cardiac output, oxygen saturation, pulmonary        arterial pressures and central venous pressure    -   Siting of a venous catheter in the cephalic vein, for infusing        pentobarbital, for liquid replacement and for blood sampling        (determination of the plasma levels of substance or other        clinical blood values)    -   Siting of a venous catheter in the saphenous vein, for infusing        fentanyl and for administration of substance    -   Infusion of vasopressin (Sigma) in increasing dosage, up to a        dose of 4 mU/kg/min. The pharmacological substances are then        tested with this dosage.

The primary signals are amplified if necessary (Gould amplifier, GouldInstrument Systems, Valley View, USA or Edwards-Vigilance-Monitor,Edwards, Irvine, USA) and subsequently fed into the Ponemah system(DataSciences Inc, Minneapolis, USA) for evaluation. The signals arerecorded continuously throughout the experimental period, and arefurther processed digitally by said software, and averaged over 30seconds.

C. Exemplary Embodiments of Pharmaceutical Compositions

The compounds according to the invention can be converted intopharmaceutical preparations in the following ways:

Tablet: Composition:

100 mg of the compound according to the invention, 50 mg of lactose(monohydrate), 50 mg of maize starch (native), 10 mg ofpolyvinylpyrrolidone (PVP 25) (from BASF, Ludwigshafen, Germany) and 2mg of magnesium stearate.

Tablet weight 212 mg, diameter 8 mm, radius of curvature 12 mm

Production:

The mixture of compound according to the invention, lactose and starchis granulated with a 5% strength solution (m/m) of the PVP in water. Thegranules are dried and then mixed with the magnesium stearate for 5minutes. This mixture is compressed in a conventional tablet press (seeabove for format of the tablet). A guideline compressive force for thecompression is 15 kN.

Suspension which can be Administered Orally:

Composition:

1000 mg of the compound according to the invention, 1000 mg of ethanol(96%), 400 mg of Rhodigel® (xanthan gum from FMC, Pennsylvania, USA) and99 g of water.

10 ml of oral suspension correspond to a single dose of 100 mg of thecompound according to the invention.

Production:

The Rhodigel is suspended in ethanol, and the compound according to theinvention is added to the suspension. The water is added while stirring.The mixture is stirred for about 6 h until the swelling of the Rhodigelis complete.

Solution which can be Administered Orally:

Composition:

500 mg of the compound according to the invention, 2.5 g of polysorbateand 97 g of polyethylene glycol 400. 20 g of oral solution correspond toa single dose of 100 mg of the compound according to the invention.

Production:

The compound according to the invention is suspended in the mixture ofpolyethylene glycol and polysorbate with stirring. The stirring processis continued until the compound according to the invention hascompletely dissolved.

i.v. Solution:

The compound according to the invention is dissolved in a concentrationbelow the saturation solubility in a physiologically tolerated solvent(e.g. isotonic saline, 5% glucose solution and/or 30% PEG 400 solution).The solution is sterilized by filtration and used to fill sterile andpyrogen-free injection containers.

1. A method for the treatment and/or prevention of acute and chronicheart failure, hypervolemic and euvolemic hyponatremia, cirrhosis of theliver, ascites, edema and the syndrome of inadequate ADH secretion(SIADH) comprising administering to a human or animal in need thereof aneffective amount of a compound of the formula (I)

in which R¹ represents (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl or(C₂-C₆)-alkynyl, each of which may be mono- to trisubstituted byidentical or different radicals selected from the group consisting offluorine, chlorine, cyano, trifluoromethyl, oxo, hydroxyl,difluoromethoxy, trifluoromethoxy, (C₁-C₄)-alkoxy, (C₃-C₇)-cycloalkyland phenyl, where (C₃-C₇)-cycloalkyl may be substituted up to two timesby identical or different radicals selected from the group consisting offluorine, trifluoromethyl, (C₁-C₄)-alkyl, oxo, hydroxyl,trifluoromethoxy and (C₁-C₄)-alkoxy and where phenyl may be substitutedup to three times by identical or different radicals selected from thegroup consisting of halogen, cyano, nitro, difluoromethyl,trifluoromethyl, (C₁-C₄)-alkyl, hydroxyl, hydroxymethyl,difluoromethoxy, trifluoromethoxy, (C₁-C₄)-alkoxy, (C₁-C₄)-alkoxymethyl,hydroxycarbonyl, (C₁-C₄)-alkoxycarbonyl, aminocarbonyl,mono-(C₁-C₄)-alkylaminocarbonyl and di-(C₁-C₄)-alkylaminocarbonyl, orrepresents (C₃-C₇)-cycloalkyl which may be mono- or disubstituted byidentical or different radicals selected from the group consisting offluorine, trifluoromethyl, (C₁-C₄)-alkyl, oxo, hydroxyl,trifluoromethoxy and (C₁-C₄)-alkoxy, Ar¹ represents phenyl, thienyl orfuryl, each of which may be mono- to trisubstituted by identical ordifferent radicals selected from the group consisting of halogen, cyano,nitro, difluoromethyl, trifluoromethyl, (C₁-C₄)-alkyl, hydroxyl,trifluoromethoxy and (C₁-C₄)-alkoxy, L¹ represents the group —CH₂—,—C(═O)— or —SO₂—, Q represents a phenyl ring, a 5-membered heteroarylring having up to three ring heteroatoms from the group consisting of N,O and S or a 6-membered heteroaryl ring having up to three nitrogen ringatoms, R² represents a substituent selected from the group consisting offluorine, chlorine, bromine, cyano, nitro, (C₁-C₄)-alkyl,(C₃-C₆)-cycloalkyl, phenyl, hydroxyl, (C₁-C₄)-alkoxy, amino,aminocarbonylamino, (C₁-C₄)-alkylcarbonylamino, hydroxycarbonyl,(C₁-C₄)-alkoxycarbonyl, aminocarbonyl, mono-(C₁-C₄)-alkylaminocarbonyland di-(C₁-C₄)-alkylaminocarbonyl, where the (C₁-C₄)-alkyl substituentfor its part may be substituted by hydroxyl, (C₁-C₄)-alkoxy,carbamoyloxy, hydroxycarbonyl, (C₁-C₄)-alkoxy-carbonyl, aminocarbonyl,mono-(C₁-C₄)-alkylaminocarbonyl or di-(C₁-C₄)-alkylaminocarbonyl or upto three times by fluorine and where the phenyl substituent for its partmay be substituted by fluorine, chlorine, cyano, methyl, trifluoromethylor methoxy, n represents the number 0, 1 or 2, where in the case thatthe substituent R² occurs twice its meanings may be identical ordifferent, L² represents a bond, represents —O— or represents a group ofthe formula —(CR^(3A)R^(3B))_(p)— in which R^(3A) represents hydrogen,fluorine or methyl, R^(3B) represents hydrogen, fluorine, (C₁-C₄)-alkyl,hydroxycarbonyl, (C₁-C₄)-alkoxycarbonyl or aminocarbonyl, where(C₁-C₄)-alkyl may be substituted by hydroxyl or carbamoyloxy or up tothree times by fluorine, or R^(3A) and R^(3B) are attached to oneanother and together form a —(CH₂)_(r) bridge in which r represents thenumber 2, 3, 4 or 5 and a CH₂ group of this bridge may be replaced by—O—, and p represents the number 1 or 2, where in the case that thegroup —CR^(3A)R^(3B)— occurs twice the individual meanings of R^(3A) andR^(3B) may in each case be identical or different, and Ar² representsphenyl, naphthyl or 5- to 10-membered heteroaryl having up to three ringheteroatoms from the group consisting of N, O and S, each of which maybe mono- to trisubstituted by identical or different radicals selectedfrom the group consisting of halogen, cyano, nitro, difluoromethyl,trifluoromethyl, (C₁-C₄)-alkyl, hydroxyl, difluoromethoxy,trifluoromethoxy and (C₁-C₄)-alkoxy, or a salt thereof.
 2. The method ofclaim 1, wherein R¹ represents (C₁-C₆)-alkyl which may be mono- totrisubstituted by identical or different radicals selected from thegroup consisting of fluorine, trifluoromethyl, oxo, hydroxyl, methoxy,ethoxy, (C₃-C₆)-cycloalkyl and phenyl, where (C₃-C₆)-cycloalkyl may besubstituted up to two times by identical or different radicals selectedfrom the group consisting of fluorine, methyl, trifluoromethyl, ethyland hydroxyl and where phenyl may be substituted up to two times byidentical or different radicals selected from the group consisting offluorine, chlorine, cyano, methyl, difluoromethyl, trifluoromethyl,ethyl, hydroxyl, methoxy, trifluoromethoxy, ethoxy, hydroxycarbonyl,methoxycarbonyl, ethoxycarbonyl and aminocarbonyl, or represents(C₂-C₆)-alkenyl or represents (C₃-C₆)-cycloalkyl which may be mono- ordisubstituted by identical or different radicals selected from the groupconsisting of fluorine, methyl, trifluoromethyl, ethyl and hydroxyl, Ar¹represents phenyl or thienyl, each of which may be mono- ordisubstituted by identical or different radicals selected from the groupconsisting of fluorine, chlorine, cyano, methyl, trifluoromethyl, ethyl,hydroxyl, methoxy, trifluoromethoxy and ethoxy, L¹ represents the group—CH₂— or —SO₂—, Q represents a phenyl ring, a 5-membered heteroaryl ringhaving up to three ring heteroatoms from the group consisting of N, Oand S or a 6-membered heteroaryl ring having up to two nitrogen ringatoms, R² represents a substituent selected from the group consisting offluorine, chlorine, bromine, (C₁-C₄)-alkyl, (C₃-C₆)-cycloalkyl, phenyl,(C₁-C₄)-alkoxy, hydroxycarbonyl, (C₁-C₄)-alkoxycarbonyl, aminocarbonyland mono-(C₁-C₄)-alkylaminocarbonyl, where the (C₁-C₄)-alkyl substituentfor its part may be substituted by hydroxyl, (C₁-C₄)-alkoxy,carbamoyloxy, hydroxycarbonyl, (C₁-C₄)-alkoxy-carbonyl or aminocarbonylor up to three times by fluorine and where the phenyl substituent forits part may be substituted by fluorine, chlorine, methyl ortrifluoromethyl, n represents the number 0 or 1, L² represents a bond orrepresents a group of the formula —(CR^(3A)R^(3B))_(p)— in which R^(3A)represents hydrogen or methyl, R^(3B) represents hydrogen,(C₁-C₄)-alkyl, hydroxycarbonyl, (C₁-C₄)-alkoxycarbonyl or aminocarbonyl,where (C₁-C₄)-alkyl may be substituted by hydroxyl or carbamoyloxy, andp represents the number 1 or 2, where in the case that the group—CR^(3A)R^(3B)— occurs twice the individual meanings of R^(3A) andR^(3B) may in each case be identical or different, and Ar² representsphenyl which may be mono- or disubstituted by identical or differentradicals selected from the group consisting of fluorine, chlorine,cyano, difluoromethyl, trifluoromethyl, (C₁-C₄)-alkyl, methoxy,difluoromethoxy, trifluoromethoxy and ethoxy, or a salt thereof.
 3. Themethod of claim 1, wherein R¹ represents (C₁-C₄)-alkyl which may bemono- or disubstituted by identical or different radicals selected fromthe group consisting of fluorine, trifluoromethyl, oxo, hydroxyl andphenyl, where phenyl for its part may be substituted by a radicalselected from the group consisting of fluorine, chlorine, methyl,trifluoromethyl, methoxy, hydroxycarbonyl and methoxycarbonyl, orrepresents allyl or cyclopropyl, Ar¹ represents phenyl or thienyl, eachof which is substituted by a radical selected from the group consistingof fluorine and chlorine, L¹ represents the group —CH₂—, Q represents apyridyl ring, a pyrimidinyl ring or an optionally substituted phenylring of the formula

or represents an optionally substituted 5-membered heteroaryl ring ofthe formula

in which * denotes the point of attachment to the group L¹ and **denotes the point of attachment to the group L², R^(2A) representshydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl,hydroxymethyl, carbamoyloxymethyl, hydroxycarbonyl, methoxycarbonyl,ethoxycarbonyl, aminocarbonyl, methylaminocarbonyl ortert-butylaminocarbonyl, R^(2B) represents hydrogen, methyl ortrifluoromethyl and R^(2C) represents hydrogen or methyl which may besubstituted by hydroxycarbonyl, methoxycarbonyl or aminocarbonyl, L²represents a bond or the group —CH₂— and Ar² represents phenyl which ismono- or disubstituted by identical or different radicals selected fromthe group consisting of fluorine, chlorine, methyl, trifluoromethyl,methoxy and trifluoromethoxy, or a salt thereof.
 4. The method of claim1, wherein R¹ represents (C₁-C₄)-alkyl which may be mono- ordisubstituted by identical or different radicals selected from the groupconsisting of fluorine, trifluoromethyl and hydroxyl, or representscyclopropyl, Ar¹ represents p-chlorophenyl, L¹ represents the group—CH₂—, Q represents a pyrimidinyl ring of the formula

or represents an optionally substituted 5-membered heteroaryl ring ofthe formula

in which * denotes the point of attachment to the group L¹ and **denotes the point of attachment to the group L², R^(2B) representshydrogen, methyl or trifluoromethyl and R^(2C) represents hydrogen ormethyl which may be substituted by hydroxycarbonyl, methoxycarbonyl oraminocarbonyl, L² represents a bond or the group —CH₂— and Ar²represents phenyl which is mono- or disubstituted by identical ordifferent radicals selected from the group consisting of fluorine,chlorine, methyl, trifluoromethyl, methoxy and trifluoromethoxy, or asalt thereof. 5-12. (canceled)
 13. The method of claim 1, wherein R¹represents (C₁-C₄)-alkyl which may be mono- or disubstituted byidentical or different radicals selected from the group consisting offluorine, trifluoromethyl, oxo and hydroxyl, or represents allyl orcyclopropyl, or a salt thereof.
 14. The method of claim 1, wherein Ar¹represents phenyl or thienyl, each of which is monosubstituted by aradical selected from the group consisting of fluorine, chlorine, cyano,methyl, trifluoromethyl, ethyl, hydroxyl, methoxy, trifluoromethoxy andethoxy, or a salt thereof.
 15. The method of claim 1, wherein thecompound of formula (I) is5-(4-Chlorophenyl)-2-{[1-(2-chlorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one,of the formula:

or a salt thereof.